Azetidinyl diamides as monoacylglycerol lipase inhibitors

ABSTRACT

Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula (I) as follows: 
                         
wherein Y, Z, R 1 , and s are defined herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 12/765,487, filed Apr. 22, 2012, currently pending, which claims priority to U.S. provisional patent application Nos. 61/171,658 and 61/171,649, each filed Apr. 22, 2009, now abandoned, which are hereby incorporated by reference in their entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The research and development of the invention described below was not federally sponsored.

BACKGROUND OF THE INVENTION

Cannabis sativa has been used for the treatment of pain for many years. Δ⁹-tetrahydrocannabinol is a major active ingredient from Cannabis sativa and an agonist of cannabinoid receptors (Pertwee, Brit J Pharmacol, 2008, 153, 199-215). Two cannabinoid G protein-coupled receptors have been cloned, cannabinoid receptor type 1 (CB₁ Matsuda et al., Nature, 1990, 346, 561-4) and cannabinoid receptor type 2 (CB₂ Munro et al., Nature, 1993, 365, 61-5). CB₁ is expressed centrally in brain areas, such as the hypothalamus and nucleus accumbens as well as peripherally in the liver, gastrointestinal tract, pancreas, adipose tissue, and skeletal muscle (Di Marzo et al., Curr Opin Lipidol, 2007, 18, 129-140). CB₂ is predominantly expressed in immune cells, such as monocytes (Pacher et al., Amer J Physiol, 2008, 294, H1133-H1134), and under certain conditions, also in the brain (Benito et al., Brit J Pharmacol, 2008, 153, 277-285) and in skeletal (Cavuoto et al., Biochem Biophys Res Commun, 2007, 364, 105-110) and cardiac (Hajrasouliha et al., Eur J Pharmacol, 2008, 579, 246-252) muscle. An abundance of pharmacological, anatomical and electrophysiological data, using synthetic agonists, indicate that increased cannabinoid signaling through CB₁/CB₂ promotes analgesia in tests of acute nociception and suppresses hyperalgesia in models of chronic neuropathic and inflammatory pain (Cravatt et al., J Neurobiol, 2004, 61, 149-60; Guindon et al., Brit J Pharmacol, 2008, 153, 319-334).

Efficacy of synthetic cannabinoid receptor agonists is well documented. Moreover, studies using cannabinoid receptor antagonists and knockout mice have also implicated the endocannabinoid system as an important modulator of nociception. Anandamide (AEA) (Devane et al., Science, 1992, 258, 1946-9) and 2-arachidinoylglycerol (2-AG) (Mechoulam et al., Biochem Pharmacol, 1995, 50, 83-90; Sugiura et al., Biochem Biophys Res Commun, 1995, 215, 89-97) are 2 major endocannabinoids. AEA is hydrolyzed by fatty acid amide hydrolase (FAAH) and 2-AG is hydrolyzed by monoacylglycerol lipase (MGL) (Piomelli, Nat Rev Neurosci, 2003, 4, 873-884). Genetic ablation of FAAH elevates endogenous AEA and results in a CB₁-dependent analgesia in models of acute and inflammatory pain (Lichtman et al., Pain, 2004, 109, 319-27), suggesting that the endocannabinoid system functions naturally to inhibit pain (Cravatt et al., J Neurobiol, 2004, 61, 149-60). Unlike the constitutive increase in endocannabinoid levels using FAAH knockout mice, use of specific FAAH inhibitors transiently elevates AEA levels and results in antinociception in vivo (Kathuria et al., Nat Med, 2003, 9, 76-81). Further evidence for an endocannabinoid-mediated antinociceptive tone is demonstrated by the formation of AEA in the periaqueductal grey following noxious stimulation in the periphery (Walker et al., Proc Natl Acad Sci USA, 1999, 96, 12198-203) and, conversely, by the induction of hyperalgesia following antisense RNA-mediated inhibition of CB₁ in the spinal cord (Dogrul et al., Pain, 2002, 100, 203-9).

With respect to 2-AG, intravenous delivery of 2-AG produces analgesia in the tail flick (Mechoulam et al., Biochem Pharmacol, 1995, 50, 83-90) and hot plate (Lichtman et al., J Pharmacol Exp Ther, 2002, 302, 73-9) assays. In contrast, it was demonstrated that 2-AG given alone is not analgesic in the hot plate assay, but when combined with other 2-monoacylglycerols (i.e., 2-linoleoyl glycerol and 2-palmitoyl glycerol), significant analgesia is attained, a phenomenon termed the “entourage effect” (Ben-Shabat et al., Eur J Pharmacol, 1998, 353, 23-31). These “entourage” 2-monoacylglycerols are endogenous lipids that are co-released with 2-AG and potentiate endocannabinoid signaling, in part, by inhibiting 2-AG breakdown, most likely by competition for the active site on MGL. This suggests that synthetic MGL Inhibitors will have a similar effect. Indeed, URB602, a relatively weak synthetic MGL Inhibitor, showed an antinociceptive effect in a murine model of acute inflammation (Comelli et al., Brit J Pharmacol, 2007, 152, 787-794).

Although the use of synthetic cannabinoid agonists have conclusively demonstrated that increased cannabinoid signaling produces analgesic and anti-inflammatory effects, it has been difficult to separate these beneficial effects from the unwanted side effects of these compounds. An alternative approach is to enhance the signaling of the endocannabinoid system by elevating the level of 2-AG, the endocannabinoid of highest abundance in the central nervous system (CNS) and gastrointestinal tract, which may be achieved by inhibition of MGL. Therefore, MGL Inhibitors are potentially useful for the treatment of pain, inflammation, and CNS disorders (Di Marzo et al., Curr Pharm Des, 2000, 6, 1361-80; Jhaveri et al., Brit J Pharmacol, 2007, 152, 624-632; McCarberg Bill et al., Amer J Ther, 2007, 14, 475-83), as well as glaucoma and disease states arising from elevated intraocular pressure (Njie, Ya Fatou; He, Fang; Qiao, Zhuanhong; Song, Zhao-Hui, Exp. Eye Res., 2008, 87(2):106-14).

SUMMARY OF THE INVENTION

The present invention is directed to a compound of Formula (I)

wherein

Y and Z are independently selected from a) or b) such that one of Y and Z is selected from group a) and the other is selected from group b);

-   -   Group a) is unsubstituted C₆₋₁₀ aryl,     -   Group b) is         -   i) C₆₋₁₀ aryl; or         -   ii) heteroaryl selected from the group consisting of             thiazolyl, pyridinyl, indolyl, indazolyl, benzoxazolyl,             benzothiazolyl, benzofuranyl, benzothienyl,             imidazo[1,2-a]pyridin-2-yl, quinolinyl, quinazolinyl,             furanyl, thienyl, oxazolyl, pyrazolyl, and benzimidazolyl;

with the proviso that a heteroaryl of Group b) is substituted with other than C₁₋₄-alkoxy;

wherein C₆₋₁₀ aryl and heteroaryl of Group b) are optionally independently substituted with one to two substitutents selected from the group consisting of bromo, chloro, fluoro, iodo, C₁₋₄alkyl, C₁₋₄alkoxy, and trifluoromethyl; and are substituted with one additional substituent selected from the group consisting of

-   -   i) C₆₋₁₀ aryl; or     -   ii) heteroaryl selected from the group consisting of         pyrimidinyl, thienyl, quinolinyl, pyridinyl, thiazolyl,         benzimidazolyl, pyrrolyl, and pyrazolyl;

wherein phenyl of the C₆₋₁₀aryl and the heteroaryl are optionally independently substituted with one to two substituents selected from the group consisting of C₁₋₄alkoxycarbonylamino; C₁₋₄alkyl; cyanomethyl; C₁₋₄alkoxy; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; C₁₋₄alkylcarbonyl; C₁₋₄alkoxycarbonyl; C₁₋₄alkoxycarbonyl(C₂₋₄)alkenyl; cyano(C₂₋₄)alkenyl; (2-cyano)ethylaminocarbonyl; cyano; carboxy; aminocarbonyl; C₁₋₄alkylaminocarbonyl; di(C₁₋₄alkyl)aminocarbonyl; formyl; nitro; bromo; hydroxy; di(C₁₋₄alkyl)aminosulfonyl; C₁₋₄alkylsulfonyl; di(C₁₋₄alkyl)aminosulfonyl; morpholin-4-ylsulfonyl; —OCH₂O— attached at adjacent carbon atoms; and NR^(c)R^(d); wherein R^(c) is hydrogen or C₁₋₆alkyl and wherein Rd is hydrogen, C₁₋₆alkyl, cyano(C₁₋₄)alkyl, C₃₋₈cycloalkyl, C₁₋₆alkylcarbonyl, C₃₋₈cycloalkylcarbonyl, C₃₋₈cycloalkyl(C₁₋₄)alkyl, aminocarbonyl, di(C₁₋₄alkyl)aminocarbonyl, C₆₋₁₀arylcarbonyl; di(C₁₋₄alkyl)aminosulfonyl, and C₁₋₄alkylsulfonyl;

s is 0, 1 or 2; provided that when s is 2, R¹ is independently selected from the group consisting of phenyl, C₁₋₃alkyl, and C₆₋₁₀aryl(C₁₋₃)alkyl;

R¹ is C₆₋₁₀aryl, C₁₋₃alkyl, benzyloxymethyl, hydroxy(C₁₋₃)alkyl, aminocarbonyl, carboxy, trifluoromethyl, spirofused cyclopropyl, 3-oxo, or aryl(C₁₋₃)alkyl; or, when s is 2 and R¹ is C₁₋₃alkyl, the C₁₋₃alkyl substituents are taken with the piperizinyl ring to form a 3,8-diaza-bicyclo[3.2.1]octanyl or 2,5-diaza-bicyclo[2.2.2]octanyl ring system;

with the proviso that when Y is phenyl, Z is other than 3-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-2-yl)phenyl, 2-(2-fluorophenyl)phenyl, 2-(4-fluorophenyl)phenyl, 4-(3-cyanophenyl)phenyl 4-(pyrazol-1-yl)phenyl, 1-ethylcarbonyl-3,4-dihydro-1H-isoquinolin-2-yl, 2-phenylethynyl, 6-bromo-imidazo[1,2-α]pyridin-2-yl,

and with the proviso that a compound of Formula (I) is other than a compound wherein Y is phenyl, Z is biphenyl-4-yl, s is 1, and R¹ is spirofused cyclopropyl; and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof.

The present invention also provides, inter alia, a pharmaceutical composition comprising, consisting of and/or consisting essentially of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and/or a pharmaceutically acceptable diluent and a compound of Formula (I) or a pharmaceutically acceptable salt form thereof.

Also provided are processes for making a pharmaceutical composition comprising, consisting of, and/or consisting essentially of admixing a compound of Formula (I) and a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and/or a pharmaceutically acceptable diluent.

The present invention further provides, inter alia, methods for treating or ameliorating a MGL-modulated disorder in a subject, including a human or other mammal in which the disease, syndrome, or condition is affected by the modulation of MGL, such as pain and the diseases that lead to such pain, inflammation and CNS disorders, using a compound of Formula (I).

The present invention also provides, inter alia, methods for producing the instant compounds and pharmaceutical compositions and medicaments thereof.

DETAILED DESCRIPTION OF THE INVENTION

With reference to substituents, the term “independently” refers to the situtaion that when more than one substituent is possible, the substituents may be the same or different from each other.

The term “alkyl” whether used alone or as part of a substituent group, refers to straight and branched carbon chains having 1 to 8 carbon atoms. Therefore, designated numbers of carbon atoms (e.g., C₁₋₈) refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent. In substituent groups with multiple alkyl groups, such as (C₁₋₆alkyl)₂-amino, the C₁₋₆alkyl groups of the dialkylamino may be the same or different.

The term “alkoxy” refers to an —O-alkyl group, wherein the term “alkyl” is as defined above.

The terms “alkenyl” and “alkynyl” refer to straight and branched carbon chains having 2 or more carbon atoms, wherein an alkenyl chain contains at least one double bond and an alkynyl chain contains at least one triple bond.

The term “cycloalkyl” refers to saturated or partially saturated, monocyclic or polycyclic hydrocarbon rings of 3 to 14 carbon atoms. Examples of such rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl.

The term “benzo-fused cycloalkyl” refers to a 5- to 8-membered monocyclic cycloalkyl ring fused to a benzene ring. The carbon atom ring members that form the cycloalkyl ring may be fully saturated or partially saturated.

The term “heterocyclyl” refers to a nonaromatic monocyclic or bicyclic ring system having 3 to 10 ring members and which contains carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S. Included within the term heterocyclyl is a nonaromatic cyclic ring of 5 to 7 members in which 1 to 2 members are nitrogen, or a nonaromatic cyclic ring of 5 to 7 members in which 0, 1 or 2 members are nitrogen and up to 2 members are oxygen or sulfur and at least one member must be either nitrogen, oxygen or sulfur; wherein, optionally, the ring contains zero to one unsaturated bonds, and, optionally, when the ring is of 6 or 7 members, it contains up to 2 unsaturated bonds. The carbon atom ring members that form a heterocycle ring may be fully saturated or partially saturated. The term “heterocyclyl” also includes two 5 membered monocyclic heterocycloalkyl groups bridged to form a bicyclic ring. Such groups are not considered to be fully aromatic and are not referred to as heteroaryl groups. When a heterocycle is bicyclic, both rings of the heterocycle are non-aromatic and at least one of the rings contains a heteroatom ring member. Examples of heterocycle groups include, and are not limited to, pyrrolinyl (including 2H-pyrrole, 2-pyrrolinyl or 3-pyrrolinyl), pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl. Unless otherwise noted, the heterocycle is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.

The term “benzo-fused heterocyclyl” refers to a 5 to 7 membered monocyclic heterocycle ring fused to a benzene ring. The heterocycle ring contains carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S. The carbon atom ring members that form the heterocycle ring may be fully saturated or partially saturated. Unless otherwise noted, benzo-fused heterocycle ring is attached to its pendant group at a carbon atom of the benzene ring.

The term “aryl” refers to an unsaturated, aromatic monocyclic or bicyclic ring of 6 to 10 carbon members. Examples of aryl rings include phenyl and naphthalenyl.

The term “heteroaryl” refers to an aromatic monocyclic or bicyclic aromatic ring system having 5 to 10 ring members and which contains carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S. Included within the term heteroaryl are aromatic rings of 5 or 6 members wherein the ring consists of carbon atoms and has at least one heteroatom member. Suitable heteroatoms include nitrogen, oxygen, and sulfur. In the case of 5 membered rings, the heteroaryl ring preferably contains one member of nitrogen, oxygen or sulfur and, in addition, up to 3 additional nitrogens. In the case of 6 membered rings, the heteroaryl ring preferably contains from 1 to 3 nitrogen atoms. For the case wherein the 6 membered ring has 3 nitrogens, at most 2 nitrogen atoms are adjacent. When a heteroaryl is bicyclic, at least one heteroatom is present in each ring. Examples of heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. Unless otherwise noted, the heteroaryl is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.

Unless otherwise noted, the term “benzo fused heteroaryl” refers to a 5 to 6 membered monocyclic heteroaryl ring fused to a benzene ring. The heteroaryl ring contains carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S. Examples of heteroaryl groups with the optionally fused benzene rings include indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl and quinazolinyl. Unless otherwise noted, the benzo-fused heteroaryl is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine and iodine.

-   -   The term “formyl” refers to the group —C(═O)H.     -   The term “oxo” refers to the group (═O).

Whenever the term “alkyl” or “aryl” or either of their prefix roots appear in a name of a substituent (e.g., arylalkyl, alkylamino) the name is to be interpreted as including those limitations given above for “alkyl” and “aryl.” Designated numbers of carbon atoms (e.g., C₁-C₆) refer independently to the number of carbon atoms in an alkyl moiety, an aryl moiety, or in the alkyl portion of a larger substituent in which alkyl appears as its prefix root. For alkyl and alkoxy substituents, the designated number of carbon atoms includes all of the independent members included within a given range specified. For example C₁₋₆ alkyl would include methyl, ethyl, propyl, butyl, pentyl and hexyl individually as well as sub-combinations thereof (e.g., C₁₋₂, C₁₋₃, C₁₋₄, C₁₋₅, C₂₋₆, C₃₋₆, C₄₋₆, C₅₋₆, C₂₋₅, etc.).

In general, under standard nomenclature rules used throughout this disclosure, the terminal portion of the designated side chain is described first followed by the adjacent functionality toward the point of attachment. Thus, for example, a “C₁-C₆ alkylcarbonyl” substituent refers to a group of the formula:

The numbering system shown below is used for describing the position of R¹ substituents on the piperazinyl ring of Formula (I):

The term “R” at a stereocenter designates that the stereocenter is purely of the R-configuration as defined in the art; likewise, the term “S” means that the stereocenter is purely of the S-configuration. As used herein, the terms “*R” or “*S” at a stereocenter are used to designate that the stereocenter is of pure but unknown configuration. As used herein, the term “RS” refers to a stereocenter that exists as a mixture of the R- and S-configurations. Similarly, the terms “*RS” or “*SR” refer to a stereocenter that exists as a mixture of the R- and S-configurations and is of unknown configuration relative to another stereocenter within the molecule.

Compounds containing one stereocenter drawn without a stereo bond designation are a mixture of 2 enantiomers. Compounds containing 2 stereocenters both drawn without stereo bond designations are a mixture of 4 diastereomers. Compounds with 2 stereocenters both labeled “RS” and drawn with stereo bond designations are a 2-component mixture with relative stereochemistry as drawn. Compounds with 2 stereocenters both labeled “*RS” and drawn with stereo bond designations are a 2-component mixture with relative stereochemistry unknown. Unlabeled stereocenters drawn without stereo bond designations are a mixture of the R- and S-configurations. For unlabeled stereocenters drawn with stereo bond designations, the absolute stereochemistry is as depicted.

Unless otherwise noted, it is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of Formula (I) as herein defined can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.

The term “subject” refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

The term “therapeutically effective amount” refers to an amount of an active compound or pharmaceutical agent, including a compound of the present invention, which elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation or partial alleviation of the symptoms of the disease, syndrome, condition, or disorder being treated.

The term “composition” refers to a product that includes the specified ingredients in therapeutically effective amounts, as well as any product that results, directly, or indirectly, from combinations of the specified ingredients in the specified amounts.

The term “MGL inhibitor” is intended to encompass a compound that interacts with MGL to substantially reduce or eliminate its catalytic activity, thereby increasing the concentrations of its substrate(s). The term “MGL-modulated” is used to refer to the condition of being affected by the modulation of the MGL enzyme including the condition of being affected by the inhibition of the MGL enzyme, such as, for example, pain and the diseases that lead to such pain, inflammation and CNS disorders.

As used herein, unless otherwise noted, the term “affect” or “affected” (when referring to a disease, syndrome, condition or disorder that is affected by inhibition of MGL) shall include a reduction in the frequency and/or severity of one or more symptoms or manifestations of said disease, syndrome, condition or disorder; and/or include the prevention of the development of one or more symptoms or manifestations of said disease, syndrome, condition or disorder or the development of the disease, condition, syndrome or disorder.

The compounds of Formula (I) are useful in methods for treating, ameliorating and/or preventing a disease, a syndrome, a condition or a disorder that is affected by the inhibition of MGL. Such methods comprise, consist of and/or consist essentially of administering to a subject, including an animal, a mammal, and a human in need of such treatment, amelioration and/or prevention, a therapeutically effective amount of a compound of Formula (I) as herein defined, or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof. In particular, the compounds of Formula (I) as herein defined are useful for treating, ameliorating and/or preventing pain; diseases, syndromes, conditions, or disorders causing such pain; inflammation and/or CNS disorders. More particularly, the compounds of Formula (I) as herein defined are useful for treating, ameliorating and/or preventing inflammatory pain, inflammatory hypersensitivity conditions and/or neuropathic pain, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), as herein defined.

Examples of inflammatory pain include pain due to a disease, condition, syndrome, disorder, or a pain state including inflammatory bowel disease, visceral pain, migraine, post operative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, labor, musculoskeletal diseases, skin diseases, toothache, pyresis, burn, sunburn, snake bite, venomous snake bite, spider bite, insect sting, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome, menstrual pain, endometriosis, pain due to physical trauma, headache, sinus headache, tension headache, or arachnoiditis.

One type of inflammatory pain is inflammatory hyperalgesia/hypersensitivity. Examples of inflammatory hyperalgesia include a disease, syndrome, condition, disorder, or pain state including inflammation, osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominal pain, musculoskeletal diseases, skin diseases, post operative pain, headaches, toothache, burn, sunburn, insect sting, neurogenic bladder, urinary incontinence, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, enteritis, irritable bowel syndrome, inflammatory bowel diseases including Crohn's Disease, ulcerative colitis, urinary incontinence, benign prostatic hypertrophy, cough, asthma, rhinitis, nasal hypersensitivity, itch, contact dermintisi and/or dermal allergy and chronic obstructive pulmonary disease.

In an embodiment, the present invention is directed to a method for treating, ameliorating and/or preventing inflammatory visceral hyperalgesia in which a enhanced visceral irritability exists, comprising, consisting of, and/or consisting essentially of the step of administering to a subject in need of such treatment a therapeutically effective amount of a compound, salt or solvate of Formula (I), as herein defined. In a further embodiment, the present invention is directed to a method for treating inflammatory somatic hyperalgesia in which a hypersensitivity to thermal, mechanical and/or chemical stimuli exists, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof

A further embodiment of the present invention is directed to a method for treating, ameliorating and/or preventing neuropathic pain. Examples of a neuropathic pain include pain due to a disease, syndrome, condition, disorder, or pain state including cancer, neurological disorders, spine and peripheral nerve surgery, brain tumor, traumatic brain injury (TBI), spinal cord trauma, chronic pain syndrome, fibromyalgia, chronic fatigue syndrome, lupus, sarcoidosis, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, central pain, neuropathies associated with spinal cord injury, stroke, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, bony fractures, oral neuropathic pain, Charcot's pain, complex regional pain syndrome I and II (CRPS I/II), radiculopathy, Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome, optic neuritis, postfebrile neuritis, migrating neuritis, segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngial neuralgia, migrainous neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, postherpetic neuralgia, causalgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia, trigeminal neuralgia, vulvodynia, or vidian neuralgia.

One type of neuropathic pain is neuropathic cold allodynia, which can be characterized by the presence of a neuropathy-associated allodynic state in which a hypersensitivity to cooling stimuli exists. Examples of neuropathic cold allodynia include allodynia due to a disease, condition, syndrome, disorder or pain state including neuropathic pain (neuralgia), pain arising from spine and peripheral nerve surgery or trauma, traumatic brain injury (TBI), trigeminal neuralgia, postherpetic neuralgia, causalgia, peripheral neuropathy, diabetic neuropathy, central pain, stroke, peripheral neuritis, polyneuritis, complex regional pain syndrome I and II (CRPS I/II) and radiculopathy.

In a further embodiment, the present invention is directed to a method for treating, ameliorating and/or preventing neuropathic cold allodynia in which a hypersensitivity to a cooling stimuli exists, comprising, consisting of, and/or consisting essentially of the step of administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula (I), as herein defined, or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof.

In a further embodiment, the present invention is directed to a method for treating, ameliorating and/or preventing CNS disorders. Examples of CNS disorders include anxieties, such as social anxiety, post-traumatic stress disorder, phobias, social phobia, special phobias, panic disorder, obsessive-compulsive disorder, acute stress, disorder, separation anxiety disorder, and generalized anxiety disorder, as well as depression, such as major depression, bipolar disorder, seasonal affective disorder, post natal depression, manic depression, and bipolar depression.

The present invention includes a pharmaceutical composition comprising a compound of Formula (I) wherein:

wherein a) Group b) is

-   -   i) C₆₋₁₀ aryl; or     -   ii) heteroaryl selected from the group consisting of thiazolyl,         pyridinyl, indolyl, indazolyl, benzoxazolyl, benzothiazolyl,         benzofuranyl, benzothienyl, quinolinyl, quinazolinyl, thienyl,         furanyl, and benzimidazolyl;         -   wherein C₆₋₁₀ aryl and heteroaryl of Group b) are optionally             independently substituted with one to two substituents             independently selected from the group consisting of bromo,             chloro, fluoro, iodo, methyl, methoxy, and trifluoromethyl,             and are substituted with one additional substituent selected             from the group consisting of     -   i) C₆₋₁₀ aryl; and     -   ii) heteroaryl selected from the group consisting of thienyl,         quinolinyl, pyridinyl, pyrazolyl, and benzimidazolyl, and         pyrrolyl;         -   wherein phenyl of the C₆₋₁₀aryl, and the heteroaryl             substituent are optionally independently substituted with             one to two substituents selected from the group consisting             of C₁₋₄alkoxycarbonylamino; C₁₋₄alkoxycarbonyl; C₁₋₄alkyl;             cyanomethyl; C₁₋₄alkoxy; one to three fluoro or chloro             substituents; trifluoromethyl; trifluoromethoxy;             C₁₋₄alkylcarbonyl; C₁₋₄alkoxycarbonyl(C₂₋₄)alkenyl;             cyano(C₂₋₄)alkenyl; (2-cyano)ethylaminocarbonyl; cyano;             carboxy; aminocarbonyl; di(C₁₋₄alkyl)aminocarbonyl; formyl;             nitro; bromo; hydroxy; di(C₁₋₄alkyl)aminosulfonyl;             C₁₋₄alkylsulfonyl; morpholin-4-ylsulfonyl; and NR^(c)R^(d)             wherein R^(c) is hydrogen or C₁₋₆alkyl and wherein R^(d) is             hydrogen, C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₆alkylcarbonyl,             di(C₁₋₄alkyl)aminosulfonyl, and C₁₋₄alkylsulfonyl;             b) Group b) is     -   i) C₆₋₁₀ aryl; or     -   ii) heteroaryl selected from the group consisting of thiazolyl,         pyridinyl, indolyl, indazolyl, benzoxazolyl, benzothiazolyl,         benzothienyl, quinolinyl, quinazolinyl, thienyl, and         benzimidazolyl;         -   wherein C₆₋₁₀ aryl and heteroaryl of Group b) are optionally             independently substituted with one to two substituents             independently selected from the group consisting of bromo,             chloro, fluoro, iodo, methyl, methoxy, and trifluoromethyl,             and are substituted with one additional substituent selected             from the group consisting of     -   i) C₆₋₁₀ aryl; and     -   ii) heteroaryl selected from the group consisting of         pyrimidinyl, thienyl, quinolinyl, pyridinyl, benzimidazolyl, and         pyrrolyl;         -   wherein phenyl of the C₆₋₁₀aryl, and the heteroaryl             substituent are optionally independently substituted with             one to two substituents selected from the group consisting             of C₁₋₄alkoxycarbonylamino; C₁₋₄alkoxycarbonyl; C₁₋₄alkyl;             cyanomethyl; C₁₋₄alkoxy; one to three fluoro or chloro             substituents; trifluoromethyl; trifluoromethoxy;             C₁₋₄alkylcarbonyl; C₁₋₄alkoxycarbonyl(C₂₋₄)alkenyl;             cyano(C₂₋₄)alkenyl; (2-cyano)ethylaminocarbonyl; cyano;             carboxy; aminocarbonyl; di(C₁₋₄alkyl)aminocarbonyl; formyl;             nitro; bromo; hydroxy; di(C₁₋₄alkyl)aminosulfonyl;             C₁₋₄alkylsulfonyl; morpholin-4-ylsulfonyl, and NR^(c)R^(d)             wherein R^(c) is hydrogen or C₁₋₆alkyl and wherein Rd is             hydrogen, C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₆alkylcarbonyl,             di(C₁₋₄alkyl)aminosulfonyl, and C₁₋₄alkylsulfonyl;             c) Group b is     -   i) C₆₋₁₀ aryl;     -   ii) heteroaryl selected from the group consisting of indolyl,         indazolyl, benzoxazolyl, benzothienyl, and thienyl;         -   wherein C₆₋₁₀ aryl and heteroaryl of Group b) are optionally             independently substituted with one to two substituents             independently selected from the group consisting of bromo,             chloro, fluoro, iodo, methyl, methoxy, and trifluoromethyl,             and are substituted with one additional substituent selected             from the group consisting of     -   i) C₆₋₁₀ aryl; and     -   ii) heteroaryl selected from the group consisting of         pyrimidinyl, thienyl, and quinolinyl;         -   wherein phenyl of the C₆₋₁₀aryl and the heteroaryl             substituent are optionally independently substituted with             one to two substituents selected from the group consisting             of C₁₋₄alkoxycarbonylamino; C₁₋₄alkoxycarbonyl; C₁₋₄alkyl;             cyanomethyl; C₁₋₄alkoxy; one to three fluoro or chloro             substituents; trifluoromethyl; trifluoromethoxy;             C₁₋₄alkylcarbonyl; C₁₋₄alkoxycarbonyl(C₂₋₄)alkenyl;             cyano(C₂₋₄)alkenyl; cyano; carboxy; aminocarbonyl;             di(C₁₋₄alkyl)aminocarbonyl; formyl; nitro; bromo; hydroxy;             di(C₁₋₄alkyl)aminosulfonyl; C₁₋₄alkylsulfonyl;             morpholin-4-ylsulfonyl; and NR^(c)R^(d) wherein R^(c) is             hydrogen or C₁₋₆alkyl and wherein Rd is hydrogen, C₁₋₆alkyl,             C₃₋₈cycloalkyl, C₁₋₆alkylcarbonyl,             di(C₁₋₄alkyl)aminosulfonyl, and C₁₋₄alkylsulfonyl;             d) s is 0 or 1;             e) s is 0;             f) R¹ is phenyl, spirofused cyclopropyl, or C₁₋₃alkyl;             g) R¹ is phenyl;

and any combination of embodiments a) through g) above, provided that it is understood that combinations in which different embodiments of the same substituent would be combined are excluded;

with the proviso that when Y is phenyl, Z is other than 3-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-2-yl)phenyl, 2-(2-fluorophenyl)phenyl, 2-(4-fluorophenyl)phenyl, 4-(3-cyanophenyl)phenyl 4-(pyrazol-1-yl)phenyl, 1-ethylcarbonyl-3,4-dihydro-1H-isoquinolin-2-yl, 2-phenylethynyl, 6-bromo-imidazo[1,2-c]pyridin-2-yl,

and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof.

An embodiment of the present invention is directed to compounds of Formula (I)

wherein

Y and Z are independently selected from a) or b) such that one of Y and Z is selected from group a) and the other is selected from group b);

Group a) is unsubstituted C₆₋₁₀ aryl;

Group b) is

-   -   i) C₆₋₁₀ aryl; or     -   ii) heteroaryl selected from the group consisting of thiazolyl,         pyridinyl, indolyl, indazolyl, benzoxazolyl, benzothiazolyl,         benzofuranyl, benzothienyl, quinolinyl, quinazolinyl, thienyl,         furanyl, and benzimidazolyl;         -   wherein C₆₋₁₀ aryl and heteroaryl of Group b) are optionally             independently substituted with one to two substituents             independently selected from the group consisting of bromo,             chloro, fluoro, iodo, methyl, methoxy, and trifluoromethyl,             and are substituted with one additional substituent selected             from the group consisting of     -   i) C₆₋₁₀ aryl; and     -   ii) heteroaryl selected from the group consisting of thienyl,         quinolinyl, pyridinyl, pyrazolyl, and benzimidazolyl, and         pyrrolyl; and         -   wherein phenyl of the C₆₋₁₀aryl, and the heteroaryl             substituent are optionally independently substituted with             one to two substituents selected from the group consisting             of C₁₋₄alkoxycarbonylamino; C₁₋₄alkoxycarbonyl; C₁₋₄alkyl;             cyanomethyl; C₁₋₄alkoxy; one to three fluoro or chloro             substituents; trifluoromethyl; trifluoromethoxy;             C₁₋₄alkylcarbonyl; C₁₋₄alkoxycarbonyl(C₂₋₄)alkenyl;             cyano(C₂₋₄)alkenyl; (2-cyano)ethylaminocarbonyl; cyano;             carboxy; aminocarbonyl; di(C₁₋₄alkyl)aminocarbonyl; formyl;             nitro; bromo; hydroxy; di(C₁₋₄alkyl)aminosulfonyl;             C₁₋₄alkylsulfonyl; morpholin-4-ylsulfonyl; and NR^(c)R^(d)             wherein R^(c) is hydrogen or C₁₋₆alkyl and wherein Rd is             hydrogen, C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₆alkylcarbonyl,             di(C₁₋₄alkyl)aminosulfonyl, and C₁₋₄alkylsulfonyl;

s is 0 or 1;

R¹ is phenyl, spirofused cyclopropyl, or C₁₋₃alkyl;

with the proviso that when Y is phenyl, Z is other than, 3-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-2-yl)phenyl, 2-(2-fluorophenyl)phenyl, 2-(4-fluorophenyl)phenyl, 4-(3-cyanophenyl)phenyl 4-(pyrazol-1-yl)phenyl, 1-ethylcarbonyl-3,4-dihydro-1H-isoquinolin-2-yl, 2-phenylethynyl, 6-bromo-imidazo[1,2-α]pyridin-2-yl,

and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof.

An embodiment of the present invention is directed to compounds of Formula (I)

wherein

Y and Z are independently selected from a) or b) such that one of Y and Z is selected from group a) and the other is selected from group b);

Group a) is unsubstituted C₆₋₁₀ aryl;

Group b) is

-   -   i) C₆₋₁₀ aryl;     -   ii) heteroaryl selected from the group consisting of thiazolyl,         pyridinyl, indolyl, indazolyl, benzoxazolyl, benzothiazolyl,         benzothienyl, quinolinyl, quinazolinyl, thienyl, and         benzimidazolyl;         -   wherein C₆₋₁₀ aryl and heteroaryl of Group b) are optionally             independently substituted with one to two substituents             independently selected from the group consisting of bromo,             chloro, fluoro, iodo, methyl, methoxy, and trifluoromethyl,             and are substituted with one additional substituent selected             from the group consisting of     -   i) C₆₋₁₀ aryl; and     -   ii) heteroaryl selected from the group consisting of         pyrimidinyl, thienyl, quinolinyl, pyridinyl, benzimidazolyl, and         pyrrolyl; and         -   wherein phenyl of the C₆₋₁₀aryl, and the heteroaryl             substituent are optionally independently substituted with             one to two substituents selected from the group consisting             of C₁₋₄alkoxycarbonylamino; C₁₋₄alkoxycarbonyl; C₁₋₄alkyl;             cyanomethyl; C₁₋₄alkoxy; one to three fluoro or chloro             substituents; trifluoromethyl; trifluoromethoxy;             C₁₋₄alkylcarbonyl; C₁₋₄alkoxycarbonyl(C₂₋₄)alkenyl;             cyano(C₂₋₄)alkenyl; (2-cyano)ethylaminocarbonyl; cyano;             carboxy; aminocarbonyl; di(C₁₋₄alkyl)aminocarbonyl; formyl;             nitro; bromo; hydroxy; di(C₁₋₄alkyl)aminosulfonyl;             C₁₋₄alkylsulfonyl; morpholin-4-ylsulfonyl; and NR^(c)R^(d)             wherein R^(c) is hydrogen or C₁₋₆alkyl and wherein Rd is             hydrogen, C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₆alkylcarbonyl,             di(C₁₋₄alkyl)aminosulfonyl, and C₁₋₄alkylsulfonyl;     -   s is 0 or 1;     -   R¹ is phenyl;

with the proviso that when Y is phenyl, Z is other than, 3-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-2-yl)phenyl, 2-(2-fluorophenyl)phenyl, 2-(4-fluorophenyl)phenyl, 4-(3-cyanophenyl)phenyl 4-(pyrazol-1-yl)phenyl, 1-ethylcarbonyl-3,4-dihydro-1H-isoquinolin-2-yl, 2-phenylethynyl, 6-bromo-imidazo[1,2-α]pyridin-2-yl,

and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof.

An embodiment of the present invention is directed to compounds of Formula (I)

wherein

Y and Z are independently selected from a) or b) such that one of Y and Z is selected from group a) and the other is selected from group b);

Group a) is unsubstituted phenyl;

Group b) is

-   -   i) C₆₋₁₀ aryl; or     -   ii) heteroaryl selected from the group consisting of indolyl,         indazolyl, benzoxazolyl, benzothienyl, and thienyl;         -   wherein C₆₋₁₀ aryl and heteroaryl of Group b) are optionally             independently substituted with one to two substituents             independently selected from the group consisting of bromo,             chloro, fluoro, iodo, methyl, methoxy, and trifluoromethyl,             and are substituted with one additional substituent selected             from the group consisting of     -   i) C₆₋₁₀ aryl; and     -   ii) heteroaryl selected from the group consisting of         pyrimidinyl, thienyl, and quinolinyl;         -   wherein phenyl of the C₆₋₁₀aryl and the heteroaryl             substituent are optionally independently substituted with             one to two substituents selected from the group consisting             of C₁₋₄alkoxycarbonylamino; C₁₋₄alkoxycarbonyl; C₁₋₄alkyl;             cyanomethyl; C₁₋₄alkoxy; one to three fluoro or chloro             substituents; trifluoromethyl; trifluoromethoxy;             C₁₋₄alkylcarbonyl; C₁₋₄alkoxycarbonyl(C₂₋₄)alkenyl;             cyano(C₂₋₄)alkenyl; cyano; carboxy; aminocarbonyl;             di(C₁₋₄alkyl)aminocarbonyl; formyl; nitro; bromo; hydroxy;             di(C₁₋₄alkyl)aminosulfonyl; C₁₋₄alkylsulfonyl;             morpholin-4-ylsulfonyl; and NR^(c)R^(d) wherein R^(c) is             hydrogen or C₁₋₆alkyl and wherein Rd is hydrogen, C₁₋₆alkyl,             C₃₋₈cycloalkyl, C₁₋₆alkylcarbonyl,             di(C₁₋₄alkyl)aminosulfonyl, and C₁₋₄-alkylsulfonyl;     -   s 0 or 1;     -   R¹ is phenyl;

with the proviso that when Y is phenyl, Z is other than, 3-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-2-yl)phenyl, 2-(2-fluorophenyl)phenyl, 2-(4-fluorophenyl)phenyl, 4-(3-cyanophenyl)phenyl 4-(pyrazol-1-yl)phenyl, 1-ethylcarbonyl-3,4-dihydro-1H-isoquinolin-2-yl, 2-phenylethynyl, 6-bromo-imidazo[1,2-α]pyridin-2-yl,

and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof.

An embodiment of the present invention is directed to compounds of Formula (I)

wherein

Y and Z are independently selected from a) or b) such that one of Y and Z is selected from group a) and the other is selected from group b);

Group a) is unsubstituted phenyl; or

Group b) is

-   -   i) C₆₋₁₀ aryl; or     -   ii) heteroaryl selected from the group consisting of indolyl,         indazolyl, benzoxazolyl, benzothienyl, and thienyl;         -   wherein C₆₋₁₀ aryl and heteroaryl of Group b) are optionally             independently substituted with one to two substituents             independently selected from the group consisting of bromo,             chloro, fluoro, iodo, methyl, methoxy, and trifluoromethyl,             and are substituted with one additional substituent selected             from the group consisting of     -   i) C₆₋₁₀ aryl; and     -   ii) heteroaryl selected from the group consisting of         pyrimidinyl, thienyl, and quinolinyl;         -   wherein phenyl of the C₆₋₁₀aryl and the heteroaryl             substituent are optionally independently substituted with             one to two substituents selected from the group consisting             of C₁₋₄alkoxycarbonylamino; C₁₋₄alkoxycarbonyl; C₁₋₄alkyl;             cyanomethyl; C₁₋₄alkoxy; one to three fluoro or chloro             substituents; trifluoromethyl; trifluoromethoxy;             C₁₋₄alkylcarbonyl; C₁₋₄alkoxycarbonyl(C₂₋₄)alkenyl;             cyano(C₂₋₄)alkenyl; cyano; carboxy; aminocarbonyl;             di(C₁₋₄alkyl)aminocarbonyl; formyl; nitro; bromo; hydroxy;             di(C₁₋₄alkyl)aminosulfonyl; C₁₋₄alkylsulfonyl;             morpholin-4-ylsulfonyl; and NR^(c)R^(d) wherein R^(c) is             hydrogen or C₁₋₆alkyl and wherein Rd is hydrogen, C₁₋₆alkyl,             C₃₋₈cycloalkyl, C₁₋₆alkylcarbonyl,             di(C₁₋₄alkyl)aminosulfonyl, and C₁₋₄alkylsulfonyl;     -   s is 0;

with the proviso that when Y is phenyl, Z is other than, 3-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-2-yl)phenyl, 2-(2-fluorophenyl)phenyl, 2-(4-fluorophenyl)phenyl, 4-(3-cyanophenyl)phenyl 4-(pyrazol-1-yl)phenyl, 1-ethylcarbonyl-3,4-dihydro-1H-isoquinolin-2-yl, 2-phenylethynyl, 6-bromo-imidazo[1,2-α]pyridin-2-yl,

and enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts thereof.

A further embodiment of the present invention is directed to a compound of Formula (I)

selected from the group consisting of:

-   a compound wherein Y is phenyl, Z is 4-biphenyl, and s is 0; -   a compound wherein Y is phenyl, Z is 4-pyrrol-1-ylphenyl, and s is     0; -   a compound wherein Y is phenyl, Z is 4-(4-fluorophenyl)phenyl, and s     is 0; -   a compound wherein Y is phenyl, Z is 4-(4-methoxyphenyl)phenyl, and     s is 0; -   a compound wherein Y is phenyl, Z is 4-(2-chlorophenyl)phenyl, and s     is 0; -   a compound wherein Y is phenyl, Z is 4-(3,4-dichlorophenyl)phenyl,     and s is 0; -   a compound wherein Y is 4-biphenyl, Z is phenyl, and s is 1, and R¹     is 3-phenyl; -   a compound wherein Y is phenyl, Z is 2-phenylbenzoxazol-6-yl, and s     is 0; -   a compound wherein Y is phenyl, Z is 6-phenyl-naphth-2-yl, and s is     0; -   a compound wherein Y is phenyl, Z is 7-phenyl-quinolin-3-yl, and s     is 0; -   a compound wherein Y is phenyl, Z is     2-(4-methoxyphenyl)benzoxazol-6-yl, and s is 0; -   a compound wherein Y is phenyl, Z is 5-phenylthien-2-yl, and s is 0; -   a compound wherein Y is phenyl, Z is 4-methyl-2-phenylthiazol-5-yl,     and s is 0; -   a compound wherein Y is phenyl, Z is     4-methyl-2-thien-2-yl-thiazol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     4-methyl-2-(4-methylphenyl)-thiazol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     4-methyl-2-(4-trifluoromethylphenyl)-thiazol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     6-(4-trifluoromethylphenyl)benzothien-2-yl, and s is 0; -   a compound wherein Y is phenyl, Z is 6-phenyl-benzothien-2-yl, and s     is 0; -   a compound wherein Y is phenyl, Z is 4-(2,4-dimethoxyphenyl)phenyl,     and s is 0; -   a compound wherein Y is phenyl, Z is     4-(3-trifluoromethylphenyl)phenyl, and s is 0; -   a compound wherein Y is penta-deuterated phenyl, Z is     4-(3-trifluoromethylphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is 4-(2-fluorophenyl)phenyl, and s     is 0; -   a compound wherein Y is phenyl, Z is 4-(3-isopropyloxyphenyl)phenyl,     and s is 0; -   a compound wherein Y is phenyl, Z is     4-(4-trifluoromethoxyphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is 4-(2-fluoropyridin-4-yl)phenyl,     and s is 0; -   a compound wherein Y is phenyl, Z is     4-(3-fluoro-4-methoxyphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is     4-(4-methoxycarbonylphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is     4-(3,4,5-trifluorophenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is     4-(3-diethylaminocarbonylphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is 4-(3-fluorophenyl)phenyl, and s     is 0; -   a compound wherein Y is phenyl, Z is     4-(2-trifluoromethoxyphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is 4-(4-methylphenyl)phenyl, and s     is 0; -   a compound wherein Y is phenyl, Z is 4-(2-isopropyloxyphenyl)phenyl,     and s is 0; -   a compound wherein Y is phenyl, Z is     4-(2-methoxycarbonylphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is     4-(4-fluoro-2-methoxyphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is 4-(2,3-dimethoxyphenyl)phenyl,     and s is 0; -   a compound wherein Y is phenyl, Z is 4-(2,5-difluorophenyl)phenyl,     and s is 0; -   a compound wherein Y is phenyl, Z is     4-(2-fluoro-6-methoxyphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is 4-(2,3-difluorophenyl)phenyl,     and s is 0; -   a compound wherein Y is phenyl, Z is     4-(3-dimethylaminosulfonylamino-phenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is     1-(4-trifluoromethylphenyl)-1H-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is 3-(thien-2-yl)phenyl, and s is     0; -   a compound wherein Y is phenyl, Z is 4-(thien-2-yl)phenyl, and s is     0; -   a compound wherein Y is phenyl, Z is 3-(pyridin-2-yl)phenyl, and s     is 0; -   a compound wherein Y is phenyl, Z is 3-(pyridin-3-yl)phenyl, and s     is 0; -   a compound wherein Y is phenyl, Z is 3-(pyridin-4-yl)phenyl, and s     is 0; -   a compound wherein Y is phenyl, Z is 4-(pyridin-3-yl)phenyl, and s     is 0; -   a compound wherein Y is phenyl, Z is     4-(2-trifluoromethylphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is     3-(2-trifluoromethylphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is     3-(4-trifluoromethylphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is     4-(4-trifluoromethylphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is     2-(4-chlorophenyl)-3H-benzimidazol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     4-(3-methanesulfonylphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is     4-(4-chloro-3-trifluoromethylphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is 4-(3-cyanophenyl)phenyl, and s     is 0; -   a compound wherein Y is phenyl, Z is 4-(3-chlorophenyl)phenyl, and s     is 0; -   a compound wherein Y is phenyl, Z is 4-(4-chlorophenyl)phenyl, and s     is 0; -   a compound wherein Y is phenyl, Z is 4-(3,5-dichlorophenyl)phenyl,     and s is 0; -   a compound wherein Y is phenyl, Z is     4-(3-methylcarbonylamino-phenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is 1-phenyl-indol-5-yl, and s is     0; -   a compound wherein Y is phenyl, Z is     1-(3-trifluoromethylphenyl)indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     2-(3-trifluoromethylphenyl)benzoxazol-6-yl, and s is 0; -   a compound wherein Y is phenyl, Z is 4-(benzimidazol-1-yl)phenyl,     and s is 0; -   a compound wherein Y is phenyl, Z is     2-methyl-4-(3-trifluoromethylphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is     3-methyl-4-(3-trifluoromethylphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is     2-fluoro-4-(3-trifluoromethylphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is     3-methoxy-4-(3-trifluoromethylphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is     2-chloro-4-(3-trifluoromethylphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is 2-phenyl-benzoxazol-5-yl, and s     is 0; -   a compound wherein Y is phenyl, Z is     2-methyl-4-(3-chloro-4-fluorophenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is     2-methyl-4-(4-chloro-3-trifluoromethylphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is     3-methyl-4-(3-chloro-4-fluorophenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is     3-methyl-4-(4-chloro-3-trifluoromethylphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is     3-methoxy-4-(3-chloro-4-fluorophenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is     3-methoxy-4-(4-chloro-3-trifluoromethylphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is     2-chloro-4-(3-chloro-4-fluorophenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is     2-chloro-4-(4-chloro-3-trifluoromethylphenyl)phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is 5-phenyl-pyridin-3-yl, and s is     0; -   a compound wherein Y is phenyl, Z is 3-fluoro-4-phenyl-phenyl, and s     is 0; -   a compound wherein Y is phenyl, Z is 4-(4-cyanophenyl)phenyl, and s     is 0; -   a compound wherein Y is phenyl, Z is 4-(4-bromophenyl)phenyl, and s     is 0; -   a compound wherein Y is phenyl, 3-chloro-6-phenyl-benzothien-2-yl,     and s is 0; -   a compound wherein Y is phenyl,     5-(4-trifluoromethyl-phenyl)-thien-2-yl, and s is 0; -   a compound wherein Y is phenyl, and Z is biphenyl-4-yl, s is 1, and     R¹ is 2(R,S)-hydroxymethyl; -   a compound wherein Y is phenyl, and Z is biphenyl-4-yl, s is 1, and     R¹ is 3(R,S)-hydroxymethyl; -   a compound wherein Y is phenyl, Z is     1-(4-cyano-3-methylphenyl)-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is 1-(4-fluorophenyl)-indol-5-yl,     and s is 0; -   a compound wherein Y is penta-deuterated phenyl, Z is     1-(4-fluorophenyl)-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     1-(4-chloro-3-fluorophenyl)-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     1-(3,4,5-trifluorophenyl)-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     3-methyl-5-phenyl-benzo[b]thien-2-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     1-(3,4-difluorophenyl)-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     3-(3-trifluoromethylphenyl)-1H-indol-6-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     1-(4-trifluoromethoxyphenyl)-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     1-(4-fluorophenyl)-3-fluoro-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     1-(4-trifluoromethylphenyl)-indazol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     1-(3-trifluoromethoxyphenyl)-indazol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is 1-phenyl-3-methyl-indol-5-yl,     and s is 0; -   a compound wherein Y is phenyl, Z is     1-(2,5-difluorophenyl)-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     1-(2,4-difluorophenyl)-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     1-(3,5-difluorophenyl)-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     4-(5-trifluoromethyl-thien-2-yl)-phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is 1-(4-cyanophenyl)-indol-5-yl,     and s is 0; -   a compound wherein Y is phenyl, Z is     1-(3-fluorophenyl)-3-methyl-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     1-(4-fluorophenyl)-3-methyl-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is 1-methyl-3-phenyl-indol-6-yl,     and s is 0; -   a compound wherein Y is phenyl, Z is     1-(5-trifluoromethylpyridin-2-yl)-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is 1-phenyl-1H-indazol-5-yl, and s     is 0; -   a compound wherein Y is phenyl, Z is 1-(2-cyanophenyl)-indol-5-yl,     and s is 0; -   a compound wherein Y is phenyl, Z is 1-phenyl-3-fluoro-indol-5-yl,     and s is 0; -   a compound wherein Y is phenyl, Z is     1-(3,4-difluorophenyl)-indazol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     3-phenyl-6-trifluoromethyl-benzothien-2-yl, and s is 0; -   a compound wherein Y is phenyl, Z is 2-phenyl-benzothiazol-6-yl, and     s is 0; -   a compound wherein Y is phenyl, Z is     1-methyl-3-(3-trifluoromethylphenyl)-indol-6-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     1-(3-aminocarbonylphenyl)-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is 1-(pyrimidin-2-yl)-indol-5-yl,     and s is 0; -   a compound wherein Y is phenyl, Z is     1-(5-fluoropyridin-2-yl)-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     4-(4-trifluoromethylphenyl)-quinazolin-7-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     1-(5-fluoropyrimidin-2-yl)-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     2-(3-fluorophenyl)-1H-benzimidazol-6-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     7-(3-fluorophenyl)-1H-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is 2-phenyl-1H-benzimidazol-4-yl,     and s is 0; -   a compound wherein Y is phenyl, Z is     2-(4-fluorophenyl)-1H-benzimidazol-4-yl, and s is 0; -   a compound wherein Y is phenyl, Z is 1-(pyridin-4-yl)-indol-5-yl,     and s is 0; -   a compound wherein Y is phenyl, Z is 4-phenyl-quinazolin-7-yl, and s     is 0; -   a compound wherein Y is phenyl, Z is 5-phenyl-benzofuran-2-yl, and s     is 0; -   a compound wherein Y is 4-biphenyl, Z is phenyl, s is 1, and R1 is     spirofused 2-cyclopropyl -   a compound wherein Y is phenyl, Z is     2-(4-chlorophenyl)-1H-benzimidazol-4-yl, -   a compound wherein Y is phenyl, Z is     2-(2-chlorophenyl)-1H-benzimidazol-4-yl, -   a compound wherein Y is phenyl, Z is     2-(3-fluorophenyl)-1H-benzimidazol-4-yl, and s is 0; -   a compound wherein Y is 4-(benzimidazol-1-yl)-phenyl, Z is phenyl,     and s is 0; -   a compound wherein Y is 2-phenyl-1H-benzimidazol-5-yl, Z is phenyl,     and s is 0; -   a compound wherein Y is phenyl, Z is 2-chloro-4-phenyl-phenyl, and s     is 0; -   a compound wherein Y is phenyl, Z is 3-methyl-4-phenyl-phenyl, and s     is 0; -   a compound wherein Y is phenyl, Z is 2-fluoro-4-phenyl-phenyl, and s     is 0; -   a compound wherein Y is phenyl, Z is 3-methoxy-4-phenyl-phenyl, and     s is 0; -   a compound wherein Y is phenyl, Z is 2-methyl-4-phenyl-phenyl, and s     is 0; -   a compound wherein Y is phenyl, Z is     1-(4-fluorophenyl)-indazol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     4-methyl-2-(3-trifluoromethylphenyl)-thiazol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     4-methyl-2-(4-chlorophenyl)-thiazol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     4-methyl-2-(3-chlorophenyl)-thiazol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     4-methyl-2-(4-fluorophenyl)-thiazol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     4-(3-trifluoromethylpyrazol-1-yl)-phenyl, and s is 0; -   a compound wherein Y is phenyl, Z is 2-methyl-5-phenyl-furan-3-yl,     and s is 0; -   a compound wherein Y is phenyl, Z is     2-trifluoromethyl-5-phenyl-furan-3-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     2-phenyl-5-trifluoromethyl-oxazol-4-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     1-phenyl-5-trifluoromethyl-pyrazol-4-yl, and s is 0; -   a compound wherein Y is phenyl, Z is 3-pyrrol-1-yl-phenyl, and s is     0; -   a compound wherein Y is phenyl, Z is 4-biphenyl, s is 1, and R1 is     3-phenyl -   a compound wherein Y is phenyl, Z is     1-(5-chloropyridin-2-yl)-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     1-(2-methylpyridin-4-yl)-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     1-(4-fluorophenyl)-6-fluoro-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     1-(4-fluorophenyl)-4-fluoro-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     1-(4-cyano-3-methoxyphenyl)-indol-5-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     3-(4-trifluoromethylphenyl)-1H-indol-6-yl, and s is 0; -   a compound wherein Y is phenyl, Z is     1-phenyl-2-methyl-benzimidazol-5-yl, and s is 0;     and enantiomers, diastereomers, solvates, and pharmaceutically     acceptable salts thereof.

For use in medicine, salts of compounds of Formula (I) as herein defined refer to non-toxic “pharmaceutically acceptable salts.” Other salts may, however, be useful in the preparation of compounds of Formula (I) as herein defined or of their pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts of compounds of Formula (I) as herein defined include acid addition salts which can, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of Formula (I) as herein defined carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts formed with suitable organic ligands, such as quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

Representative acids and bases that may be used in the preparation of pharmaceutically acceptable salts include acids including acetic acid, 2,2-dichloroactic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; and bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholin, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

Embodiments of the present invention include prodrugs of compounds of Formula (I) as herein defined. In general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound. Thus, in the methods of treating or preventing embodiments of the present invention, the term “administering” encompasses the treatment or prevention of the various diseases, conditions, syndromes and disorders described with the compound specifically disclosed or with a compound that may not be specifically disclosed, but which converts to the specified compound in vivo after administration to a patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to embodiments of this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention. The skilled artisan will understand that the term compound as used herein, is meant to include solvated compounds of Formula I.

Where the processes for the preparation of the compounds according to certain embodiments of the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-1-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.

One embodiment of the present invention is directed to a composition, including a pharmaceutical composition, comprising, consisting of, and/or consisting essentially of the (+)-enantiomer of a compound of Formula (I) as herein defined wherein said composition is substantially free from the (−)-isomer of said compound. In the present context, substantially free means less than about 25%, preferably less than about 10%, more preferably less than about 5%, even more preferably less than about 2% and even more preferably less than about 1% of the (−)-isomer calculated as.

${{\%( + )} - {enantiomer}} = {\frac{\left( {{{mass}( + )} - {enantiomer}} \right)}{\left( {{{mass}( + )} - {enantiomer}} \right) + \left( {{{mass}( - )} - {enantiomer}} \right)} \times 100.}$

Another embodiment of the present invention is a composition, including a pharmaceutical composition, comprising, consisting of, and consisting essentially of the (−)-enantiomer of a compound of Formula (I) as herein defined wherein said composition is substantially free from the (+)-isomer of said compound. In the present context, substantially free from means less than about 25%, preferably less than about 10%, more preferably less than about 5%, even more preferably less than about 2% and even more preferably less than about 1% of the (+)-isomer calculated as

${{\%( - )} - {enantiomer}} = {\frac{\left( {{{mass}( - )} - {enantiomer}} \right)}{\left( {{{mass}( + )} - {enantiomer}} \right) + \left( {{{mass}( - )} - {enantiomer}} \right)} \times 100.}$

During any of the processes for preparation of the compounds of the various embodiments of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, Second Edition, J. F. W. McOmie, Plenum Press, 1973; T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

Even though the compounds of embodiments of the present invention (including their pharmaceutically acceptable salts and pharmaceutically acceptable solvates) can be administered alone, they will generally be administered in admixture with a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient and/or a pharmaceutically acceptable diluent selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice. Thus, particular embodiments of the present invention are directed to pharmaceutical and veterinary compositions comprising compounds of Formula (I) as herein defined and at least one pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, and/or pharmaceutically acceptable diluent

By way of example, in the pharmaceutical compositions of embodiments of the present invention, the compounds of Formula (I) as herein defined may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilizing agent(s), and combinations thereof.

Solid oral dosage forms, such as tablets or capsules, containing the compounds of the present invention may be administered in at least one dosage form at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations.

Additional oral forms in which the present inventive compounds may be administered include exilirs, solutions, syrups, and suspensions; each optionally containing flavoring agents and coloring agents.

Alternatively, compounds of Formula (I) as herein defined can be administered by inhalation (intratracheal or intranasal) or in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. For example, they can be incorporated into a cream comprising, consisting of, and/or consisting essentially of an aqueous emulsion of polyethylene glycols or liquid paraffin. They can also be incorporated, at a concentration of between about 1% and about 10% by weight of the cream, into an ointment comprising, consisting of, and/or consisting essentially of a white wax or white soft paraffin base together with any stabilizers and preservatives as may be required. An alternative means of administration includes transdermal administration by using a skin or transdermal patch.

The pharmaceutical compositions of the present invention (as well as the compounds of the present invention alone) can also be injected parenterally, for example intracavernosally, intravenously, intramuscularly, subcutaneously, intradermally or intrathecally. In this case, the compositions will also include at least one of a suitable carrier, a suitable excipient, and a suitable diluent.

For parenteral administration, the pharmaceutical compositions of the present invention are best used in the form of a sterile aqueous solution that may contain other substances, for example, enough salts and monosaccharides to make the solution isotonic with blood.

For buccal or sublingual administration, the pharmaceutical compositions of the present invention may be administered in the form of tablets or lozenges, which can be formulated in a conventional manner.

By way of further example, pharmaceutical compositions containing at least one of the compounds of Formula (I) as herein defined as the active ingredient can be prepared by mixing the compound(s) with a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, and/or a pharmaceutically acceptable excipient according to conventional pharmaceutical compounding techniques. The carrier, excipient, and diluent may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral, etc.). Thus for liquid oral preparations, such as suspensions, syrups, elixirs and solutions, suitable carriers, excipients and diluents include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers, excipients and diluents include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations also may be optionally coated with substances, such as, sugars, or be enterically-coated so as to modulate the major site of absorption and disintegration. For parenteral administration, the carrier, excipient and diluent will usually include sterile water, and other ingredients may be added to increase solubility and preservation of the composition. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives, such as solubilizers and preservatives.

A therapeutically effective amount of a compound of Formula (I) as herein defined or a pharmaceutical composition thereof includes a dose range from about 0.1 mg to about 3000 mg, or any particular amount or range therein, in particular from about 1 mg to about 1000 mg, or any particular amount or range therein, or, more particularly, from about 10 mg to about 500 mg, or any particular amount or range therein, of active ingredient in a regimen of about 1 to about 4 times per day for an average (70 kg) human; although, it is apparent to one skilled in the art that the therapeutically effective amount for a compound of Formula (I) as herein defined will vary as will the diseases, syndromes, conditions, and disorders being treated.

For oral administration, a pharmaceutical composition is preferably provided in the form of tablets containing about 0.01, about 10, about 50, about 100, about 150, about 200, about 250, and about 500 milligrams of a compound of Formula (I) as herein defined.

Advantageously, a compound of Formula (I) as herein defined may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three and four times daily.

Optimal dosages of a compound of Formula (I) as herein defined to be administered may be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation and the advancement of the disease, syndrome, condition or disorder. In addition, factors associated with the particular subject being treated, including subject gender, age, weight, diet and time of administration, will result in the need to adjust the dose to achieve an appropriate therapeutic level and desired therapeutic effect. The above dosages are thus exemplary of the average case. There can be, of course, individual instances wherein higher or lower dosage ranges are merited, and such are within the scope of this invention.

Compounds of Formula (I) as herein defined may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of a compound of Formula (I) as herein defined is required for a subject in need thereof.

As MGL Inhibitors, the compounds of Formula (I) as herein defined are useful in methods for treating and preventing a disease, a syndrome, a condition or a disorder in a subject, including an animal, a mammal and a human in which the disease, the syndrome, the condition or the disorder is affected by the modulation of the MGL enzyme. Such methods comprise, consist of and/or consist essentially of administering to a subject, including an animal, a mammal, and a human in need of such treatment or prevention a therapeutically effective amount of a compound, salt or solvate of Formula (I) as herein defined. In particular, the compounds of Formula (I) as herein defined are useful for preventing or treating pain, or diseases, syndromes, conditions, or disorders causing such pain, or for treating inflammation or CNS disorders.

Examples of inflammatory pain include pain due to a disease, condition, syndrome, disorder, or a pain state, including inflammatory bowel disease, visceral pain, migraine, post operative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, labor pain, musculoskeletal diseases, skin diseases, toothache, pyresis, burn, sunburn, snake bite, venomous snake bite, spider bite, insect sting, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome, menstrual pain, endometriosis, pain, pain due to physical trauma, headache, sinus headache, tension headache, or arachnoiditis.

Examples of CNS disorders include anxieties, such as social anxiety, post-traumatic stress disorder, phobias, social phobia, special phobias, panic disorder, obsessive-compulsive disorder, acute stress, disorder, separation anxiety disorder, and generalized anxiety disorder, as well as depression, such as major depression, bipolar disorder, seasonal affective disorder, post natal depression, manic depression, and bipolar depression.

GENERAL SYNTHETIC METHODS

Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and illustrated in the schemes and examples that follow. Since the schemes are an illustration, the invention should not be construed as being limited by the chemical reactions and conditions described in the schemes. The various starting materials used in the schemes and examples are commercially available or may be prepared by methods well within the skill of persons versed in the art. The variables are as defined herein.

Abbreviations used in the instant specification, particularly the schemes and examples, are as follows:

AcCl acetyl chloride AcOH glacial acetic acid aq. aqueous Bn or Bzl benzyl CAN ceric ammonium nitrate conc. concentrated DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC N,N′-dicyclohexyl-carbodiimide DCE 1,2-dichloroethane DCM dichloromethane DIAD diisopropyl azodicarboxylate DIPEA diisopropyl-ethyl amine DMF N,N-dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride ESI electrospray ionization EtOAc ethyl acetate EtOH ethanol h hour(s) HATU O-(1H-7-azabenzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate HBTU O-(1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate HEK human embryonic kidney HPLC high performance liquid chromatography mCPBA meta-chloroperoxybenzoic acid MeCN acetonitrile MeOH methanol MeOTf methyl triflate MHz megahertz min minute(s) MS mass spectrometry NBS N-bromosuccinimide NMR nuclear magnetic resonance PyBrOP bromo-tris-pyrrolidinophosphonium hexafluorophosphate RP reverse-phase R_(t) retention time TEA or Et₃N triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TMS tetramethylsilane

Scheme A illustrates a route for the synthesis compounds of Formula (I)-A, wherein R¹, s, Y, and Z are as defined herein.

A compound of formula A1, wherein PG is a conventional amino protecting group, such as Boc, Fmoc, Cbz, and the like, is either commercially available or may be prepared by known methods described in the scientific literature. A compound of formula A1 in the presence of a non-nucleophilic base, such as pyridine, may be treated with trifluoroacetic anhydride to afford a compound of formula A2. Removal of the protecting group (PG) by conventional methods affords a compound of formula A3. A compound of formula A3 may be treated with a compound of formula A4 in the presence of a hindered amine base, such as DIPEA, to afford a compound of formula A5. Treatment of a compound of formula A5 with 1-chloroethyl chloroformate followed by methanolysis affords the corresponding amine of formula A6. Similarly, when the R¹ substituent of a compound of formula A5 is hydroxy(C₁₋₃)alkyl, the benzhydryl group may be removed by hydrogenation in the presence of a palladium catalyst to afford the amine of formula A6. A compound of formula A6 may be coupled with a carboxylic acid of formula A7 wherein Q is hydroxy, in the presence of an appropriate coupling agent such as HATU, DCC, EDC, HBTU, PyBrOP, and the like; optionally in the presence of a base such as DIPEA, to afford an amide of formula A8. Similarly, an acid chloride of formula A7 wherein Q is chloro may be used to effect the acylation of a compound of formula A6. In such case a non-nucleophilic base such as pyridine may be added to afford an amide of formula A8. Removal of the trifluoroacetyl group of a compound of formula A8 may be accomplished by the action of potassium carbonate or TEA in the presence of an alcoholic solvent such as methanol to afford a compound of formula A9. A compound of formula A9 may be acylated with a carboxylic acid or acid chloride of formula A10, wherein Q is hydroxy or chloride, respectively. Appropriate coupling conditions when using a compound of formula A10 (wherein Q is OH) include a coupling agent, such as HATU, DCC, EDC, HBTU, PyBrOP, and the like; and a base such as DIPEA to afford a compound of Formula (I)-A. When the acylation is effected by the addition of the corresponding acid chloride, the addition of a non-nucleophilic base such as pyridine affords a compound of Formula (I)-A.

Scheme B illustrates an alternate route for the synthesis compounds of Formula (I)-A, wherein R¹, s, Y, and Z are as defined herein.

A compound of formula A1, wherein PG is a conventional amino protecting group, such as Boc, Fmoc, Cbz, and the like, is either commercially available or may be prepared by known methods described in the scientific literature. A compound of formula A1 may be acylated with a compound of formula A10 using methods and reagents previously described in Scheme A to afford a compound of formula B1. Upon conventional removal of the protecting group PG, a compound of formula B2 may be treated with a compound of formula A4 in the presence of a hindered amine base such as DIPEA using the methods described in Scheme A to afford a compound of formula B3. Treatment of a compound of formula B3 with 1-chloroethyl chloroformate followed by methanolysis affords the corresponding amine of formula B4. Similarly, when the R¹ substituent of a compound of formula B3 is hydroxy(C₁₋₃)alkyl, the benzhydryl group may be removed by hydrogenation in the presence of a palladium catalyst to afford the amine of formula B4. An acylation reaction with a compound of formula A7 using the methods described in Scheme A affords the corresponding compound of Formula (I)-A.

Scheme C illustrates an alternate route for the synthesis compounds of Formula (I)-A, wherein R¹, s, Y, and Z are as defined herein.

A compound of formula B2 may be treated with a ketone of formula C1 in the presence of decaborane or a reducing agent, such as sodium triacetoxyborohydride, to afford a compound of formula C2. Removal of the Boc-amino protecting group, using conventional reagents and methods, affords a compound of formula B4. Coupling with a compound of formula A7 as described herein provides a compound of Formula (I)-A.

Scheme D illustrates a route for the synthesis compounds of Formula (I)-A, wherein R¹, s, Y, and Z are as defined herein.

A compound of formula A1, wherein PG is a conventional amino protecting group, such as Boc, Fmoc, Cbz, and the like, is either commercially available or may be prepared by known methods described in the scientific literature. A compound of formula A1 may be treated with a compound of formula A4 to afford a compound of formula D1. Upon conventional removal of protecting group PG, a compound of formula D2 may be coupled with a compound of formula A10 (wherein Q is OH) in the presence of a coupling agent, such as HATU, DCC, EDC, HBTU, PyBrOP, and the like; optionally in the presence of a base such as DIPEA, to afford a compound of formula B3. When the acylation is effected by the addition of the corresponding acid chloride, the addition of a non nucleophilic base, such as pyridine, affords a compound of formula B3. Removal of the benzhydryl group as described herein, followed by acylation with a compound of formula A7 affords a compound of Formula (I)-A.

One skilled in the art will recognize that the synthetic sequences of Schemes A, B, C and D may be altered so that the acylation with a compound of formula A7 precedes removal of the benzhydryl group, which is then followed by acylation with a compound of formula A10, thus reversing the order for introduction of groups Y and Z.

Scheme E illustrates a route for the synthesis compounds of Formula (I)-E, wherein R¹, s, and Y are as defined herein, and Z is a C₆₋₁₀aryl ring or heteroaryl group, substituted with an optionally substituted C₆₋₁₀aryl or heteroaryl group, as defined herein.

A compound of formula C1 may be deprotected using conventional methods to afford the corresponding free amine of formula E1. Coupling with a carboxylic acid of formula E2, (wherein Ar_(E) is a C₆₋₁₀aryl or heteroaryl group, and said Ar_(E) is substituted with one bromo, chloro, or iodo substitutent), in the presence of a coupling agent, such as HATU, DCC, EDC, HBTU, PyBrOP, and the like; optionally in the presence of a base such as DIPEA, affords a compound of formula E3. A ketone of formula E3 may undergo a reductive amination with a compound of formula A1 in the presence of decaborane, sodium triacetoxyborohydride, and the like, to afford a compound of formula E4. Upon conventional removal of the protecting group PG, the free amine of formula E5 may be acylated with a compound of formula A10 as described herein to afford a compound of formula E6. The substituted Ar_(E) substituent of formula E6 may be treated with an appropriately substituted Ar_(E1)-boronic acid or ester (E7), or an appropriately substituted trialkyltin reagent, trialkylsilane, and the like (wherein Ar_(E1) is an optionally substituted C₆₋₁₀aryl or heteroaryl as defined herein), using one of a variety of coupling reactions (e.g., Suzuki, Stille, and Hiyama reactions) that are well known to those versed in the art; in the presence of a suitable catalyst; and in the presence of a base such as cesium carbonate, sodium bicarbonate, potassium fluoride, and the like; to afford a compound of the Formula (I)-E.

Scheme F illustrates a route for the synthesis of compounds of Formula (I)-F, wherein R¹, s, and Y are as defined herein, and Z is an optionally substituted C₆₋₁₀aryl(C₁₋₆)alkyl or C₆₋₁₀aryl(C₂₋₆)alkenyl group, wherein L is (C₁₋₆)alkyl or (C₂₋₆)alkenyl, respectively.

A compound of formula B4 may be coupled with a commercially available compound of formula F2 (wherein Ar_(F) is an optionally substituted C₆₋₁₀aryl substituent as defined herein) in the presence of a coupling agent, such as HATU, DCC, EDC, HBTU, PyBrOP, and the like; optionally in the presence of a base, such as DIPEA; to afford a compound of Formula (I)-F.

Scheme G illustrates a route for the synthesis of compounds of Formula (I)-G and Formula (I)-G1, wherein R¹, s, and Y are as defined herein, and Z is either an optionally substituted C₆₋₁₀aryl (Ar_(G)) substituted with phenyl(C₂₋₆)alkynyl (Formula (I)-G) or an optionally substituted C₆₋₁₀aryl substituted with phenyl(C₁₋₆)alkyl.

A compound of Formula G1 may be prepared according to the methods described herein, wherein Ar_(G) is C₆₋₁₀aryl and X is a substituent selected from bromo or iodo. An X-substituted Ar_(G) ring may be cross-coupled with a compound of formula G2 in the presence of a palladium catalyst, copper iodide, and a base such as triethylamine to afford a compound of Formula (I)-G. The alkynyl functionality of a compound of Formula (I)-G may be reduced to the corresponding alkyl group by transition metal catalyzed hydrogenation, using a transition metal such as palladium on carbon, palladium (II) hydroxide, or platinum, under a hydrogen gas atmosphere, to afford a compound of Formula (I)-G1.

Scheme H illustrates a route for the synthesis of compounds of Formula (I)-H, H1, H2, and H3, wherein R¹, s, and Y are as defined herein, and Z is a benzofused heterocyclyl attached via the benzo ring, wherein the heterocyclyl portion contains a nitrogen atom, and wherein the nitrogen atom is optionally substituted. For illustrative purposes only, a 1,2,3,4-tetrahydroisoquinolinyl group has been selected to represent a nitrogen-containing benzofused heterocyclyl of the present invention.

A compound of formula B4 may be coupled with a carboxylic acid-substituted benzofused heterocyclyl of formula H1 (wherein PG is a conventional amino protecting group) to afford a compound of formula H2. Deprotection of the amino functionality of a compound of formula H2 affords the corresponding amine of Formula (I)-H, which may be derivatized using a variety of synthetic methods to form additional compounds of the present invention. For example, a compound of Formula (I)-H may be treated with an appropriately substituted sulfonyl chloride of formula H3 in the presence of an organic base to afford a compound of Formula (I)-H1 (wherein R_(H2) is phenyl or C₁₋₆alkyl. Additionally, a compound of the Formula (I)-H2 may be prepared by alkylation of the amino functionality of a compound of Formula (I)-H with an alkylating agent of formula H4 (wherein R_(H3) is phenyl or C₁₋₆alkylcarbonyl) in the presence of a base. LG of a compound of formula H4 is a common leaving group, such as a bromide, iodide, tosylate, mesylate, and the like. A compound of Formula (I)-H2 may also be prepared by a reductive amination with a compound of formula H5 in the presence of a reducing agent, such as sodium triacetoxy borohydride. A compound of Formula (I)-H3 may be prepared via a peptide coupling reaction between a compound of Formula (I)-H and an appropriately substituted carboxylic acid of formula H6 (wherein R_(H) is an optionally substituted cyclohexyl, C₁₋₆alkyl, or phenyl as defined herein) in the presence of a suitable coupling agent. Finally, compounds of Formula (I)-H4 of the present invention, wherein Ar_(H) is pyrimidine or an appropriately substituted phenyl group, may be prepared by the treatment of a compound of Formula (I)-H with a compound of formula H7 (wherein X_(H) is a group such as chloro, bromo, or iodo and Ar_(H) is as defined herein) in the presence of a transition metal catalyst, such as palladium acetate, a suitable phosphine ligand, such as BINAP, and a base, such as potassium t-butoxide.

Scheme I illustrates a route for the synthesis of compounds of Formula (I)-I, wherein R¹, s, and Y are as defined herein and Z is a C₆₋₁₀aryl substituted with C₆₋₁₀aryl(C₁₋₄)alkoxy as defined herein. For illustrative purposes only, the Z—C₆₋₁₀aryl ring is depicted as a phenyl group.

A commercially available compound of formula I1 may be converted to a compound of formula I2 by the action of a chlorinating agent such as oxalyl chloride, thionyl chloride, and the like. A compound of formula B4 may be acylated with a compound of formula I2 to afford a compound of formula I3. Removal of the acetyl functionality of a compound of formula I3 by hydrolysis in the presence of a nucleophilic base like lithium hydroxide, affords the corresponding compound of formula I4. Alkylation with a compound of formula I5 (wherein Ar₁ is an optionally substituted C₆₋₁₀aryl group and X_(I) is I, Br, Cl, or tosylate) affords a compound of Formula (I)-I. Similarly, Mitsunobu chemistry with a compound of formula I6 (wherein X₁ is hydroxy) may be used to prepare a compound of Formula (I)-I.

Scheme J illustrates a route for the synthesis of compounds of Formula (I)-J, wherein R¹, s, and Y are as defined herein, and Z is a C₆₋₁₀aryl substituted with C₆₋₁₀aryl(C₁₋₄)alkylthio as defined herein. For illustrative purposes only, the Z C₆₋₁₀aryl ring is depicted as a phenyl group.

A compound of formula J1 is either commercially available or may be prepared by known methods described in the scientific literature. A compound of formula J1 may be alkylated with a compound of formula I5 (wherein X_(j) is I, Br, Cl, or tosylate) to afford a compound of formula J2. Saponification of a compound of formula J2 affords a compound of formula J3 (wherein Q_(J) is hydroxy), which may be coupled with a compound of formula B4; or the carboxylic acid may first be converted to its corresponding acid chloride of formula J3 (wherein Q_(J) is chloro) followed by the acylation of a compound of formula B4; to afford a compound of Formula (I)-J.

Scheme K illustrates a route for the synthesis of compounds of Formula (I)-K, wherein R¹, s, and Y are as defined herein, and Z is an optionally substituted C₆₋₁₀aryl, further substituted with phenyloxy, and wherein phenyloxy is optionally substituted with C₁₋₄alkyl, trifluoromethyl, or one to two chloro substituents as defined herein. For illustrative purposes only, the Z C₆₋₁₀aryl ring is depicted as a phenyl group.

A compound of formula K1 is either commercially available or may be prepared by known methods described in the scientific literature. A compound of formula K1, or an optionally substituted derivative thereof, may be coupled with an aryl boronic acid of formula K2 (wherein Ar_(K) is phenyl optionally substituted with C₁₋₄alkyl, trifluoromethyl, or one to two chloro substituents), in the presence of a copper catalyst, such as copper iodide or copper (II) acetate, appropriate ligands, such as pyridine, 1,10-phenanthroline, ethylene diamine and the like, and an organic base, such as triethylamine, to afford a compound of formula K3. Alternatively, compounds of formula K3 may be prepared by nucleophilic aromatic displacement of an appropriately substituted methyl halobenzoate derivative, wherein the preferred halogen substituent is fluoro, with Ar_(K)-OH, wherein Ar_(K) is as previously defined, in the presence of a base. Saponification followed by optional treatment with an appropriate chlorinating agent affords a compound of formula K4 wherein Q_(K) is hydroxy or chloro. Acylation of a compound of formula B4 with a compound of formula K4 affords a compound of Formula (I)-K.

Scheme L illustrates a route for the synthesis of compounds of Formula (I)-L, wherein R¹, s, and Y are as defined herein, and Z is an optionally substituted C₆₋₁₀aryl substituted with phenylthio, wherein phenylthio is optionally substituted with C₁₋₄alkyl, trifluoromethyl, or one to two chloro substituents as defined herein. For illustrative purposes only, the Z C₆₋₁₀aryl ring is depicted as a phenyl group.

A compound of formula L1 is either commercially available or may be prepared by known methods described in the scientific literature. An aryl bromide of formula L1, or an optionally substituted derivative thereof, may be cross coupled with a compound of formula L2 (wherein Ar_(L) is phenyl optionally substituted with C₁₋₄alkyl, trifluoromethyl, or one to two chloro substituents), in the presence of a palladium catalyst, such as palladium tetrakis(triphenylphosphine), appropriate ligands, such as triphenylphosphine, and a base, such as potassium t-butoxide, to afford a compound of formula L3. Saponification of the methyl ester affords a compound of formula L4. A compound of formula B4 may be coupled with a compound of formula L4 in the presence of an appropriate peptide coupling agent such as DCC, EDC, HBTU, PyBrOP, and the like to afford a compound of Formula (I)-L.

Scheme M illustrates a route for the synthesis of compounds of Formula (I)-M, wherein R¹, s, and Y are as defined herein, and Z is a C₆₋₁₀aryl substituted with phenylsulfonyl. For illustrative purposes only, the Z C₆₋₁₀aryl ring is depicted as a phenyl group.

A compound of formula M1 may be prepared according to the methods described in Scheme L. Oxidation of the thioether functionality may be accomplished by the action of an appropriate oxidizing agent, such as mCPBA, hydrogen peroxide, and the like, to afford a compound of formula M2. Upon saponification, and subsequent peptide coupling with a compound of formula B4, a compound of Formula (I)-M may be prepared.

Scheme N illustrates a route for the synthesis of compounds of Formula (I)-N, wherein R¹, s, and Y are as defined herein and Z is C₆₋₁₀aryl substituted with a 5 to 8 membered heterocyclyloxy optionally substituted at a nitrogen atom with phenylcarbonyl, C₁₋₄alkylcarbonyl, or C₁₋₄alkoxycarbonyl. For illustrative purposes only, the Z—C₆₋₁₀aryl ring is depicted as a phenyl group.

A compound of formula I4 may be coupled with a compound of formula N1 (wherein R_(N) is phenyl, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylamino, C₁₋₄dialkylamino, or N-containing heterocyclyl attached via the nitrogen atom) under Mitsunobu conditions in an aprotic organic solvent, such as THF, to afford a compound of Formula (I)-N. Mitsunobu coupling may also be performed between 14 and a compound of formula N2, where PG is a conventional amino protecting group, such as Boc, Fmoc, Cbz, and the like. Subsequent removal of the protecting group (PG) by conventional methods affords a compound of formula N3, which may be derivatized using a variety of synthetic methods to form additional compounds of the present invention. For example, a compound of formula N3 may be coupled with a carboxylic acid (Q is hydroxy, R_(N) is phenyl or C₁₋₄alkyl), acid chloride (Q is chloride, R_(N) is phenyl or C₁₋₄alkyl), chloroformate (Q is chloride, R_(N) is C₁₋₄alkoxy), or carbamoyl chloride (Q is chloride, R_(N) is C₁₋₄alkylamino, C₁₋₄dialkylamino, or N-containing heterocyclyl attached via the nitrogen atom) of formula N4 as described herein to provide a compound of Formula (I)-N. Additionally, a compound of formula N3 may be reacted with a sulfamoyl chloride of formula N5, where R_(N2) is C₁₋₄alkylamino, C₁₋₄dialkylamino, or N-containing heterocyclyl attached via the nitrogen atom, to afford a compound of Formula (I)-N2.

Scheme O illustrates a route for the synthesis of compounds of Formula (I)-O, wherein R¹, s, and Y are as defined herein, and Z is an optionally substituted C₆₋₁₀aryl, further substituted with R¹, wherein R¹ is (1-R²)-pyrrolidin-3-yloxy, C₁₋₄alkyl, or C₆₋₁₀aryl(C₁₋₄)alkyl. For illustrative purposes only, the Z—C₆₋₁₀aryl ring is depicted as a phenyl group.

A compound of formula O1 may be coupled with a compound of formula O2 (wherein X_(O) is hydroxy) under Mitsunobu conditions to afford a compound of formula O3. Alkylation may also be achieved via a nucleophilic displacement reaction with a compound of formula O2 (wherein X_(O) is I, Br, Cl, or tosylate) in the presence of a base to afford a compound of formula O3. Saponification of the methyl ester of a compound of formula O3 affords the corresponding carboxylic acid of formula O4. A compound of formula O4 may be coupled with a compound of formula B4 as described herein to afford a compound of Formula (I)-O. Furthermore, a compound of formula O3, where R_(O) is (1-R²)-pyrrolidin-3-yloxy and R² is a conventional amino protecting group, may be deprotected and additionally derivatized on the pyrrolidine nitrogen as described herein to afford, after conversion to a compound of formula O4 and subsequent coupling with a compound of formula B4, a compound of Formula (I)-O.

Scheme P illustrates a route for the synthesis of compounds of Formula (I)-P, wherein R¹, s, and Y are as defined herein, and Z is C₆₋₁₀aryl substituted with phenyl-(Q)-C₁₋₆alkyl wherein Q is O, S, or NH; and phenyl of phenyl-(Q)-C₁₋₆alkyl is optionally independently substituted with one to two substitutents selected from bromo, chloro, fluoro, iodo, C₁₋₄alkyl, C₁₋₄alkoxy, and trifluoromethyl.

A compound of formula P1 (wherein X_(P) is hydroxy, chloro, or bromo) is either commercially available or may be prepared by known methods described in the scientific literature. A compound of formula P1 may undergo an alkylation via Mitsunobu reaction or nucleophilic displacement chemistry with a compound of formula P2 to afford a compound of formula P3. Saponification of the methyl ester of a compound of formula P3 affords the corresponding carboxylic acid of formula P4. A compound of formula P4 may be coupled with a compound of formula B4 as described herein to afford a compound of Formula (I)-P.

Scheme Q illustrates the preparation of certain useful intermediates of formula A7 (Q is hydroxy) wherein Z is a heteroaryl substituted with an optionally substituted aryl group (Ar_(Q)). For illustrative purposes only, the heteroaryl ring is represented by an indole.

A compound of formula Q1 is either commercially available or may be prepared by known methods described in the scientific literature. The compound Q1 may be treated with an aryl iodide of formula Q2 in the presence of copper iodide, trans-N,N′-dimethylcyclohexane-1,2-diamine, and potassium phosphate to afford a compound of formula Q3. Subsequent saponification affords useful carboxylic acid intermediates of formula Q4.

Scheme R illustrates the preparation of certain useful intermediates of formula A7 (Q is hydroxy) wherein Z is a benzimidazolyl or benzoxazolyl, and Z is substituted with an optionally substituted aryl or heteroaryl group (Ar_(R)) or with Ar_(R)(C₁₋₄)alkyl.

A compound of formula R1 is either commercially available or may be prepared by known methods described in the scientific literature. The compound R1 may be treated with an aryl or heteroaryl substituted carboxylic acid of formula R2 in the presence of a coupling agent such as DCC, and a hindered base such as DMAP, in an aprotic organic solvent to afford a compound of formula R3. Acid catalyzed ring closure of a compound of formula R3 affords the substituted benzimidazole or benzoxazole of formula R4 or R6, respectively. Subsequent saponification affords useful carboxylic acid intermediates of formula R5 or R7.

Scheme S illustrates the preparation of certain useful intermediates of formula A7 (Q is hydroxy) wherein Z is an optionally substituted benzothienyl group, and R_(S) represents appropriate substituents as defined in Formula (I).

A compound of formula S1 is either commercially available or may be prepared by known methods described in the scientific literature. The compound of formula S1 may be treated with thionyl chloride in an aprotic organic solvent, followed by treatment with methanol to afford a compound of formula S2. Subsequent saponification affords useful carboxylic acid intermediates of formula S3. One skilled in the art will recognize that asymmetrically substituted compounds of formula S1 could lead to mixtures of positional isomers upon cyclization with thionyl chloride. The isomers may then be separated and isolated using conventional chromatography known to those skilled in the art.

Scheme T illustrates the preparation of certain useful intermediates of formula A7 (Q is hydroxy) wherein Z is a C₆₋₁₀aryl (Ar_(T)) substituted by an optionally substituted C₆₋₁₀arylmethyl group.

A compound of formula T1 is either commercially available or may be prepared by known methods described in the scientific literature. The compound of formula T1 may be treated with an appropriately substituted organometallic reagent, such as an Ar_(T1)-methylzinc chloride of formula T2, in the presence of a palladium catalyst to afford a compound of formula T3. Subsequent saponification affords useful carboxylic acid intermediates of formula T4.

Scheme U illustrates the preparation of certain useful intermediates of formula A7 (Q is hydroxy) wherein Z is a benzothienyl group substituted with a fluoro substituent and an optionally substituted C₆₋₁₀aryl or heteroaryl group (Ar_(E1)).

A compound of formula U1 is either commercially available or may be prepared by known methods described in the scientific literature. The compound of formula U1 may be cross-coupled with a boronic acid or ester (E7) in the presence of a palladium catalyst; and in the presence of a suitable base such as potassium carbonate to afford a compound of formula U2. Saponification affords the corresponding carboxylic acid U3, which may be treated with N-fluorobenzenesulfonimide in the presence of an organometallic base such as n-butyllithium, to afford the fluorinated compound of formula U4.

Scheme V illustrates the preparation of certain useful intermediates of formulae V6, V8, and V10 (Q is hydroxy) wherein Z is a benzimidazolyl group substituted with an Ar_(V) group (wherein Ar_(V) is an optionally substituted aryl or heteroaryl substituent as defined in Formula (I)) and optionally substituted in the 2-position with methyl or oxo.

A compound of formula V1 is either commercially available or may be prepared by known methods described in the scientific literature. The compound of formula V1 may be treated with a compound of formula V2 to afford a compound of formula V3. The amino group may be reduced by the action of tin chloride in an alcoholic solvent, or by palladium catalyzed hydrogenation to afford the diamine of formula V4. Treatment with trimethyl orthoformate affords a benzimidazole of formula V5, which may be saponified to afford a compound of formula V6.

A compound of formula V4 may be treated with trimethyl orthoacetate followed by saponification to afford the corresponding 2-methyl substituted benzimidazole, V8. Similarly, a compound of formula V4 may be treated with 1,1′-carbonyldiimidazole in DMF, followed by saponification to afford the corresponding 2-oxo substituted benzimidazole, V10.

Example 1

A. 4-(2,2,2-Trifluoro-acetyl)-piperazine-1-carboxylic acid tert-butyl ester, 1c

To a solution of piperazine-1-carboxylic acid tert-butyl ester (1a, 10 g, 53.69 mmol) and pyridine (8.7 mL, 107.57 mmol) in CH₂Cl₂ (100 mL) was added dropwise compound 1b (10.5 mL, 75.54 mmol) at 0° C. The mixture was stirred at 0° C. for 2 h. 2N HCl (60 mL) was added to the mixture. The organic layer was dried over MgSO₄, filtered, and then concentrated. The crude compound 1c was used in the next reaction without further purification. MS m/z (MH⁺-Boc) 183.1, (MH⁺-C₄H₉) 227.1; ¹H NMR (300 MHz, CDCl₃): δ 3.45-3.7 (m, 8H), 1.5 (s, 9H).

B. 2,2,2-Trifluoro-1-piperazin-1-yl-ethanone, 1d. To a solution of compound 1c

(15.15 g, 53.69 mmol) in CH₂Cl₂ (60 mL) was added trifluoroacetic acid (18 mL) at room temperature. The mixture was stirred at room temperature for 18 h. The solvent was removed by evaporation. Ether (100 mL) was added to the residue. The white solid was collected by filtration, washed with ether, and dried under vacuum. The crude compound 1d was used in the next reaction without further purification. MS m/z (M+H⁺) 183.1.

C. 1-[4-(1-Benzhydryl-azetidin-3-yl)-piperazin-1-yl]-2,2,2-trifluoro-ethanone, 1f

To a solution of compound 1d (6 g, 32.94 mmol) and compound 1e (12.5 g, 39.38 mmol) in CH₃CN (60 mL) was added DIPEA (12 mL, 68.89 mmol) at room temperature. The mixture was refluxed for 2 h. The solvent was removed by evaporation and the residue was partitioned between CH₂Cl₂ and aq NaHCO₃. The organic layer was washed with aq NaHCO₃ (2×) and then extracted with 1N HCl (2×). The aqueous layer was cooled and then the pH adjusted with 1N NaOH until basic (pH=10). The mixture was extracted with CH₂Cl₂ (2×). The organic layer was dried over MgSO₄ and concentrated. Compound 1f was purified by reverse phase chromatography. MS m/z (M+H⁺) 404.2.

D. 1-(4-Azetidin-3-yl-piperazin-1-yl)-2,2,2-trifluoro-ethanone, 1g

To a solution of compound 1f (2.11 g, 5.23 mmol) in CH₂Cl₂ (60 mL) was added 1-chloroethyl chloroformate (2.0 mL, 18.35 mmol) at 0° C. under N₂. The mixture was stirred at 0° C. for 90 min and then MeOH (4 mL) was added. The mixture was refluxed for 1 h. Upon cooling, Et₂O (50 mL) was added to the mixture. The resulting solid was collected by filtration and dried. The crude compound 1g was used in the next reaction without further purification. MS m/z (M+H⁺) 238.1.

E. 1-{4-[1-(4-Cyclohexyl-benzoyl)-azetidin-3-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone, 1i

To a solution of compound 1g (2.5 g, 10.54 mmol) and HATU (4 g, 10.52 mmol) in DMF (25 mL) was added DIPEA (5 mL, 28.70 mmol). The mixture was stirred at room temperature for 30 min, and then compound 1h (2 g, 9.79 mmol) was added to the mixture. The reaction was stirred at room temperature for 18 h. Water (40 mL) was added to the reaction. The mixture was extracted with EtOAc (2×20 mL). The organic layer was dried over MgSO₄, filtered, and concentrated. The crude compound 1i was purified by reverse phase chromatography. MS m/z (M+H⁺) 424.2.

F. (4-Cyclohexyl-phenyl)-(3-piperazin-1-yl-azetidin-1-yl)-methanone, 1j

To a solution of compound 1i (0.95 g, 2.24 mmol) in CH₃OH (16 mL) and H₂O (4 mL) was added K₂CO₃ (0.8 g, 5.79 mmol). The mixture was stirred at room temperature for 1 h. After filtration, the solvent was removed by evaporation. The crude compound 1j was used in the next reaction without further purification. MS m/z (M+H⁺) 328.2.

G. 1-{1-[(4-Cyclohexylphenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)-piperazine, Cpd 1

To a solution of compound 1j (0.08 g, 0.24 mmol) and HATU (0.093 g, 0.24 mmol) in DMF (3 mL) was added DIPEA (0.1 mL). The mixture was stirred at room temperature for 30 min, and then compound 1k (0.03 g, 0.25 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 18 h. Water (6 mL) was added to the mixture. The mixture was extracted with EtOAc (2×6 mL). The organic layer was dried over MgSO₄, filtered, and concentrated. The crude compound 1 was purified by reverse phase chromatography. ¹H NMR (300 MHz, CD₃OD): δ 7.58 (d, 2H), 7.44-7.53 (m, 5H), 7.34 (d, 2H), 4.6 (m, 1H), 4.42 (m, 2H), 4.27 (m, 1H), 3.85 (m, 5H), 3.05 (m, 4H), 2.57 (m, 1H), 1.85 (m, 5H), 1.45 (m, 5H). MS m/z (M±H⁺) 432.3.

Following the procedure described above for Example 1 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Characterization Data 2 1-{1-[(4-Cyclohexylphenyl)carbonyl]azetidin-3-yl}-4-(furan- 2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.71 (d, 1H), 7.59 (d, 2H), 7.34 (d, 2H), 7.13 (d, 1H), 6.62 (dd, 1H), 4.62 (m, 1H), 4.52 (m, 1H), 4.42 (m, 1H), 4.31 (m, 1H), 4.05 (m, 4H), 3.98(m, 1H), 3.18 (m, 4H), 2.58 (m, 1H), 1.84 (m, 5H), 1.24-1.52 (m, 5H) MS m/z (M + H⁺) 422.2 3 1-{1-[(4-Cyclohexylphenyl)carbonyl]azetidin-3-yl}-4-[(1- methyl-1H-imidazol-2-yl)carbonyl]piperazine MS m/z (M + H⁺) 436.2 4 1-{1-[(4-Cyclohexylphenyl)carbonyl]azetidin-3-yl}-4- (pyridin-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 433.2 5 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.65 (m, 4H), 7.56 (d, 2H), 7.25-7.46 (m, 8H), 4.58 (m, 1H), 4.49 (m, 1H), 4.35 (m, 1H), 4.26 (m, 1H), 3.92 (m, 1H), 3.78 (m, 4H), 3.09 (m, 4H) MS m/z (M + H⁺) 426.1 6 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(furan-2- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.66 (m, 4H), 7.62 (d, 1H), 7.56 (d, 2H), 7.38 (t, 2H), 7.30 (m, 1H), 7.03 (d, 1H), 6.51 (dd, 1H), 4.56 (m, 1H), 4.44 (m, 1H), 4.33 (m, 1H), 4.22 (m, 1H), 3.95 (m, 4H), 3.81 (m, 1H), 3.01 (m, 4H) MS m/z (M + H⁺) 416.2 7 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 8.97 (s, 1H), 8.14 (s, 1H), 7.66 (m, 4H), 7.56 (d, 2H), 7.37 (t, 2H), 7.30 (m, 1H), 4.60 (m, 1H), 4.49 (m, 1H), 4.37 (m, 1H), 4.27 (m, 1H), 4.08 (m, 4H), 3.95 (m, 1H), 3.14 (m, 4H) MS m/z (M + H⁺) 433.2 8 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,3-thiazol-5- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.08 (s, 1H), 8.11 (s, 1H), 7.66 (m, 4H), 7.56 (d, 2H), 7.38 (t, 2H), 7.30 (m, 1H), 4.54 (m, 1H), 4.39 (m, 1H), 4.31 (m, 1H), 4.17 (m, 1H), 3.84 (m, 4H), 3.73 (m, 1H), 2.92 (m, 4H) MS m/z (M + H⁺) 433.2 9 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.88 (d, 1H), 7.78 (d, 1H), 7.66 (m, 4H), 7.57 (d, 2H), 7.38 (t, 2H), 7.30 (m, 1H), 4.62 (m, 3H), 4.48 (m, 1H), 4.37 (m, 1H), 4.26 (m, 1H), 3.91 (m, 3H), 3.13 (m, 4H) MS m/z (M + H⁺) 433.2 10 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(2-methyl-1,3- thiazol-4-yl)carbonyl]piperazine MS m/z (M + H⁺) 447.1 11 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(1-methyl-1H- pyrrol-2-yl)carbonyl]piperazine MS m/z (M + H⁺) 429.3 12 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(5-bromofuran- 2-yl)carbonyl]piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.76 (m, 4H), 7.66 (d, 2H), 7.47 (t, 2H), 7.39 (m, 1H), 7.11 (d, 1H), 6.64 (d, 1H), 4.66 (m, 1H), 4.57 (m, 1H), 4.44 (m, 1H), 4.34 (m, 1H), 3.91-4.10 (m, 5H), 3.17 (m, 4H) MS m/z (M + H⁺) 494.1/496.0 13 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(thiophen-2- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.75 (m, 4H), 7.61-7.72 (m, 3H), 7.34-7.52 (m, 4H), 7.14 (t, 1H), 4.65 (m, 1H), 4.52 (m, 1H), 4.42 (m, 1H), 4.29 (m, 1H), 3.96 (m, 4H), 3.90 (m, 1H), 3.07 (m, 4H) MS m/z (M + H⁺) 432.1 (calculated for C₂₅H₂₅N₃O₂S, 431.56) 14 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(5- methylthiophen-2-yl)carbonyl]piperazine MS m/z (M + H⁺) 446.1 15 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(5- bromothiophen-2-yl)carbonyl]piperazine MS m/z (M + H⁺) 510.1/512.1 16 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(5- chlorothiophen-2-yl)carbonyl]piperazine MS m/z (M + H⁺) 466.1/467.1 17 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(3- bromothiophen-2-yl)carbonyl]piperazine MS m/z (M + H⁺) 510.0/512.1 18 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(4- bromothiophen-2-yl)carbonyl]piperazine MS m/z (M + H⁺) 510.0/512.1 19 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(thieno[3,2- b]thiophen-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 488.1 20 1-(1-Benzothiophen-2-ylcarbonyl)-4-[1-(biphenyl-4- ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 482.1 21 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(3- methoxythiophen-2-yl)carbonyl]piperazine MS m/z (M + H⁺) 462.1 22 1-{1-[(4-Bromo-2-methylphenyl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 442.22/444.19 23 1-{1-[(4-Bromo-3-methoxyphenyl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 465.0/467.1 24 1-{1-[(4-Bromo-3-methoxyphenyl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 458.1/460.0 25 1-{1-[(4-Bromo-2-chlorophenyl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 469.04/471.04 26 1-{1-[(4-Bromo-2-chlorophenyl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 462.11/464.11 581 1-(Phenylcarbonyl)-4-[1-({4-[5-(trifluoromethyl)thiophen-2- yl]phenyl}carbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 500 1382 2-Phenyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole MS m/z (M + H⁺) 474 1071 1-(1,3-Thiazol-4-ylcarbonyl)-4-[1-({4-[5- (trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)azetidin-3- yl]piperazine MS m/z (M + H⁺) 507 1361 1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[5- (trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)azetidin-3- yl]piperazine MS m/z (M + H⁺) 507

Example 1a

H. Methyl 1-(4-fluorophenyl)-indole-5-carboxylate, 1m

A mixture of methyl indole-5-carboxylate 1j (0.5 g, 2.85 mmol), 1-bromo-4-fluoro-benzene 1k (2 mL, 18.21 mmol), CuI (0.544 g, 2.85 mmol), and K₂CO₃ (0.591 g, 4.28 mmol) was heated under microwave at 220° C. for 2.5 hours. The reaction mixture was diluted with CH₂Cl₂ and filtered. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 15% EtOAc/heptane) to give 1m (0.58 g).

I. 1-(4-fluorophenyl)-indole-5-carboxylic acid, 1n

A mixture of methyl 1-(4-fluorophenyl)-indole-5-carboxylate 1m (0.58 g, 2.15 mmol) and LiOH H₂O (0.36 g, 8.6 mmol) in THF (15 mL) and H₂O (10 mL) was stirred at room temperature for 5 days. Aqueous 10% HCl solution was added to the reaction mixture to adjust pH=3˜4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na₂SO₄ and concentrated to give 1n (0.5 g).

J. 1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole, Cpd 487

The title compound, Cpd 487, was prepared according to Example 1 using intermediate 1n from Example 1a and intermediate 1g in Example 1 as starting materials. ¹H NMR (400 MHz, CD₃OD): δ 8.00 (d, J=1.2 Hz, 1H), 7.88 (d, J=3 Hz, 1H), 7.55 (m, 2H), 7.46 (m, 3H), 7.34 (d, J=3 Hz, 1H), 7.27-7.21 (m, 2H), 6.74 (d, J=3 Hz, 1H), 4.52 (bs, 1H), 4.43-4.20 (m, 4H), 4.14 (m, 1H), 3.95-3.80 (m, 2H), 3.25 (m, 1H), 2.60-2.40 (m, 4H). MS m/z (M+H⁺) 490.

Following the procedure described above for Example 1a, steps H and I, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Following the procedure described above for Example 1a, step J, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the invention were prepared:

Cpd Cpd Name and Data 567 1-(4-Fluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indole ¹H NMR (400 MHz, CD₃OD): d 7.99 (s, 1H), 7.55-7.21 (m, 12H), 6.73 (s, 1H), 4.37 (bs, 1H), 4.25 (m, 2H), 4.10 (bs, 1H), 3.90 (bs, 1H), 3.75 (bs, 1H), 3.48 (bs, 2H), 3.24 (m, 1H), 2.50-2.20 (m, 4H). MS m/z (M + H⁺) 483 587 1-Phenyl-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1H-indazole MS m/z (M + H⁺) 466 579 1-(2,4-Difluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 501 1356 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-[3-(trifluoromethyl)phenyl]-1H-indole. MS m/z (M + H⁺) 540 1408 5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-[3-(trifluoromethyl)phenyl]-1H-indole MS m/z (M + H⁺) 540 1357 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole ¹H NMR (400 MHz, CD₃OD): d 8.00 (s, 1H), 7.88 (d, J = 3 Hz, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 7.59 (s, 2H), 7.54 (d, J = 3 Hz, 1H), 7.41 (d, J = 3.5 Hz, 1H), 6.79 (d, J = 3.5 Hz, 1H), 4.53 (bs, 1H), 4.43 (m, 2H), 4.28 (m, 2H), 4.14 (bs, 1H), 3.86 (m, 2H), 3.26 (m, 1H), 2.50 (m, 4H). MS m/z (M + H⁺) 540 1358 1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 490 1359 5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole MS m/z (M + H⁺) 540 1163 1-Phenyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indazole MS m/z (M + H⁺) 473 1360 1-Phenyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indazole ¹H NMR (400 MHz, CD₃OD): d 8.27 (s, 1H), 8.11 (s, 1H), 7.88 (d, J = 3 Hz, 1H), 7.77 (m, 2H), 7.72 (d, J = 8 Hz, 2H), 7.56 (m, 3H), 7.41 (t, J = 8 Hz, 1H), 4.53 (bs, 1H), 4.44-4.28 (m, 4H), 4.15 (m, 1H), 3.86 (m, 2H), 3.28 (m, 1H), 2.50 (m, 4H). MS m/z 490 (M + H⁺) MS m/z (M + H⁺) 473 1364 1-(2,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 508 1139 1-(2,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole ¹H NMR (CDCl₃, 400 MHz): d = 8.79 (d, J = 2.0 Hz, 1 H), 7.93-8.09 (m, 2 H), 7.39-7.64 (m, 2 H), 7.18-7.34 (m, 2 H), 6.98-7.16 (m, 2 H), 6.76 (d, J = 3.1 Hz, 1 H), 4.20-4.51 (m, 3 H), 4.13 (d, J = 3.9 Hz, 1 H), 3.92 (br. s., 3 H), 3.67-3.84 (m, 1 H), 3.18-3.32 (m, 1 H), 2.49 (br. s., 4 H). MS m/z (M + H⁺) 508 1061 1-(2,4-Difluorophenyl)-5-({3-[4-(1H-pyrrol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 490

Following the procedure described above for Example 1a, steps H and I, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Following the procedure described above for Example 1a, step J, with the exception of using dioxane as a solvent in step A, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 595 5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1-pyrimidin-2-yl-1H-indole MS m/z (M + H⁺) 467 598 1-(5-Fluoropyrimidin-2-yl)-5-({3-[4- (phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 485 1174 1-Pyrimidin-2-yl-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole ¹H NMR (CDCl₃, 400 MHz): d = 8.83 (d, J = 8.6 Hz, 1 H), 8.73 (d, J = 4.7 Hz, 2 H), 8.33 (d, J = 3.9 Hz, 1 H), 7.80-8.02 (m, 2 H), 7.64 (dd, J = 8.8, 1.8 Hz, 1 H), 7.54 (d, J = 3.1 Hz, 1 H), 7.10 (t, J = 4.9 Hz, 1 H), 6.75 (d, J = 3.5 Hz, 1 H), 4.03-4.72 (m, 6 H), 3.86 (m, 2 H), 3.08-3.37 (m, 1 H), 2.31- 2.68 (m, 3 H). MS m/z (M + H⁺) 474 1201 1-Pyrimidin-2-yl-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 474 1248 1-(5-Fluoropyrimidin-2-yl)-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 492 1147 1-(5-Fluoropyrimidin-2-yl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 492

Example 1b

K. Methyl 1-(3,4-difluorophenyl)-indole-5-carboxylate, 1p

A mixture of methyl indole-5-carboxylate 1j (2 g, 11.4 mmol), 1-iodo-3,4-difluoro-benzene 1o (1.5 mL, 12.5 mmol), CuI (0.22 g, 1.14 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.54 mL, 3.43 mmol), and K₃PO₄ (6.06 g, 28.5 mmol) in toluene (12 mL) was heated at 110° C. for 7 hours. The reaction mixture was diluted with CH₂Cl₂ and filtered. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 20% EtOAc/heptane) to give 1p (3.0 g).

L. 1-(3,4-Difluorophenyl)-indole-5-carboxylic acid, 1q

A mixture of methyl 1-(3,4-difluorophenyl)-indole-5-carboxylate 1p (3.0 g, 10.4 mmol) and LiOH (1.0 g, 41.8 mmol) in THF (120 mL) and H₂O (60 mL) was stirred at room temperature for 5 days. Aqueous 10% HCl solution was added to the reaction mixture to adjust pH=3˜4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na₂SO₄ and concentrated to give 1q (2.85 g).

M. 1-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole, Cpd 1362

The title compound, Cpd 1362, was prepared according to Example 1 using intermediate 1q from Example 1b and intermediate 1g in Example 1 as starting materials. ¹H NMR (CDCl₃, 400 MHz): d=7.99 (d, J=1.6 Hz, 1H), 7.88 (d, J=3.1 Hz, 1H), 7.44-7.64 (m, 3H), 7.18-7.44 (m, 4H), 6.75 (d, 1H), 4.47-4.63 (m, 1H), 4.19-4.47 (m, 4H), 4.07-4.19 (m, 1H), 3.89 (br. s., 2H), 3.18-3.33 (m, 1H), 2.50 (t, J=5.1 Hz, 4H). MS m/z (M+H⁺) 508.

Following the procedure described above for Example 1b, steps K and L, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Following the procedure described above for Example 1b, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1363 1-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole ¹H NMR (CDCl₃, 400 MHz): d = 8.79 (d, J = 2.0 Hz, 1 H), 8.00 (dd, J = 11.5, 1.8 Hz, 2 H), 7.44-7.65 (m, 2 H), 7.18- 7.42 (m, 4 H), 6.75 (d, J = 3.5 Hz, 1 H), 4.20-4.46 (m, 3 H), 4.13 (br. s., 1 H), 3.93 (br. s., 3 H), 3.67-3.85 (m, 1 H), 3.17-3.36 (m, 1 H), 2.49 (br. s., 4 H) MS m/z 508 (M + H⁺) 1366 1-(3,4-Difluorophenyl)-5-({3-[4-(1H-pyrrol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole ¹H NMR (CDCl₃, 400 MHz): d = 9.42-9.61 (m, 1 H), 7.99 (s, 1 H), 7.54-7.64 (m, 1 H), 7.45-7.54 (m, 1 H), 7.15-7.43 (m, 4 H), 6.93 (s, 1 H), 6.75 (d, J = 3.1 Hz, 1 H), 6.52 (br. s., 1 H), 6.18-6.31 (m, 1H), 4.19-4.42 (m, 3 H), 4.08-4.19 (m, 1 H), 3.90 (br. s., 4 H), 3.24 (s, 1 H), 2.34-2.56 (m, 4 H) MS m/z 490 (M + H⁺) 603 5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1-pyridin-4-yl-1H-indole MS m/z (M + H⁺) 466.1 630 1-(2-Methylpyridin-4-yl)-5-({3-[4- (phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)- 1H-indole MS m/z (M + H⁺) 480.1 1192 1-Pyridin-3-yl-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 473.2 1247 1-Pyridin-3-yl-5-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 456.3 1127 1-Pyridin-4-yl-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 473.0 1072 1-(6-Methoxypyridin-3-yl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 503.2 1176 1-(6-Methoxypyridin-3-yl)-5-({3-[4-(1H-pyrrol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 485.4 1105 1-(6-Methylpyridin-3-yl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 487.3 1181 1-(6-Methylpyridin-3-yl)-5-({3-[4-(1H-pyrrol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 469.3 1062 5-({3-[4-(1H-Pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-1H- indole MS m/z (M + H⁺) 523.2 1312 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-1H- indole MS m/z (M + H⁺) 541.3 1107 1-(2-Methoxypyridin-4-yl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 503.0 1263 1-Pyrimidin-5-yl-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 474.1 1410 1-(2-Methylpyridin-4-yl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 487.0 586 5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-indole MS m/z (M + H⁺) 534.1 596 1-(5-Fluoropyridin-2-yl)-5-({3-[4- (phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)- 1H-indole MS m/z (M + H⁺) 484.0 1135 1-Pyridin-2-yl-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 473.2 1189 1-Pyridin-2-yl-5-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 455.2 1073 1-(5-Methylpyridin-2-yl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 509.0 1126 1-(6-Methylpyridin-2-yl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 487.3 1128 1-(4-Methylpyridin-2-yl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 487.2 1216 1-(2-Methylpyrimidin-4-yl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 488.0 1314 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-[5-(trifluoromethyl)pyridin-2-yl]-1H- indole MS m/z (M + H⁺) 541.0 1121 1-(5-Fluoropyridin-2-yl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 491.0 1197 1-(4-Methylpyridin-2-yl)-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 487.1 1337 5-({4-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]piperazin- 1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole ¹H NMR (400 MHz, CDCl₃): δ 9.06 (s, 1H); 8.4 (s, 1H); 7.9-7.68 (m, 8H); 7.4 (ar, 1H); 4.97 (m, 2H); 4.45 (m, 2H); 4.16 (bs, 1H); MS m/z (M + H⁺) 508.0 1338 5-({4-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin- 1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole ¹H NMR (400 MHz, CDCl₃): δ 7.91 (m, 1H); 7.81 (m, 4H); 7.70 (m, 2H); 7.60 (m, 2H); 7.30 (m, 1H); 6.75 (m, 1H); 5.01-4.84 (m, 2H); 4.37 (m, 2H); 4.09 (bm, 1H) MS m/z (M + H⁺) 540.2 1339 5-({3-[4-(1H-Pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole MS m/z (M + H⁺) 522.2 1097 5-({3-[4-(Isothiazol-5-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole ¹H NMR (400 MHz, CDCl₃): δ 8.44 (s, 1H); 7.94 (s, 1H); 7.80 (m, 2H); 7.69 (m, 2H); 7.59 (m, 2H); 7.49 (m, 2H); 6.77 (m, 1H); 4.65-4.15 (bm, 3H); 3.81 (bm, 4H); 3.0 (bm, 4H) MS m/z (M + H⁺) 540.2 1230 1-(4-Fluorophenyl)-3-methyl-5-({4-[1-(1,3-thiazol-4- ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 504.1 1089 1-(4-Fluorophenyl)-3-methyl-5-({4-[1-(1,3-thiazol-2- ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H- indole ¹H NMR (400 MHz, CDCl₃): δ 7.92 (d, 1H); 7.78 (d, 1H); 7.69 (m, 1H); 7.42 (m, 3H); 7.21 (m, 6H); 4.94 (m, 1H); 4.40 (dd, 1H); 4.25 (dd, 1H); 4.0 (bm, 1H); 3.85 (bm, 3H); 3.15 (bm, 3H); 2.3 (s, 3H) MS m/z (M + H⁺) 504.1 1120 5-({4-[1-(1H-Pyrrol-2-ylcarbonyl)azetidin-3-yl]piperazin- 1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole MS m/z (M + H⁺) 522.1 1134 1-(3,4-Difluorophenyl)-3-methyl-5-({4-[1-(1,3-thiazol-2- ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H- indole ¹H NMR (400 MHz, CDCl₃): δ 8.0 (s, 1H); 7.86 (s, 1H); 7.80 (s, 1H); 7.62-7.42 (m, 3H); 7.36 (m, 3H); 5.05 (m, 1H); 4.5 (m, 1H); 4.35 (m, 1H); 4.08 (bm, 1H); 3.94 (bm, 4H); 3.24 (m, 3H) MS m/z (M + H⁺) 522.2 1219 1-(3,4-Difluorophenyl)-3-methyl-5-({4-[1-(1H-pyrrol-2- ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 465.1

Example 1c

N. 1-(5-Methylpyridin-2-yl)-5-({3-[4-(trifluoroacetyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole; Cpd 1184

The title compound, Cpd 1184, was prepared according to Example 1 using intermediate 1r from Example 1b and intermediate 1g in Example 1 as starting materials. MS m/z (M+H⁺) 472.1

Following the procedure described above for Example 1c, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Salt Cpd Cpd Name and Data Form 1409 1-(5-Chloropyridin-2-yl)-5-({3-[4- N-TFA (trifluoroacetyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1H-indole MS m/z (M + H⁺) 492.1 1199 1-(4-Methylpyridin-2-yl)-5-({3-[4- N-TFA (trifluoroacetyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1H-indole MS m/z (M + H⁺) 472.1 656 1-(1-{[3-Chloro-6-(trifluoromethyl)-1- N-TFA benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4- (trifluoroacetyl)piperazine MS m/z (M + H⁺) 500.1 1079 1-(4-Fluorophenyl)-5-({3-[4- N-TFA (trifluoroacetyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1H-indole MS m/z (M + H⁺) 475.2

Example 1d

O. Methyl 2-phenyl-benzooxazole-6-carboxylate, 1u

A mixture of methyl 4-amino-3-hydroxy-benzoate is (0.3 g, 1.8 mmol) and benzoyl chloride 1t (0.23 mL, 2.0 mmol) in dioxane (2.5 mL) was heated at 210° C. under microwave for 15 min. The reaction mixture was diluted with CH₂Cl₂ and washed with aq. NaHCO₃. The organic solution was dried over Na₂SO₄, concentrated and purified by flash column chromatography (silica gel, 20% EtOAc/heptane) to give 1u (0.39 g).

P. 2-Phenyl-benzooxazole-6-carboxylic acid, 1v

A mixture of methyl 2-phenyl-benzooxazole-6-carboxylate 1u (0.37 g, 1.46 mmol) and LiOH (0.10 g, 4.2 mmol) in THF (4 mL), MeOH (4 mL), and H₂O (4 mL) was stirred at room temperature for 6 h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3-4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na₂SO₄ and concentrated to give 1t (0.34 g).

Following the procedure described above for Example 1d and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Following the procedure described above for Example 1, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1141 2-Phenyl-6-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole MS m/z (M + H⁺) 474 1151 6-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-2-[3-(trifluoromethyl)phenyl]-1,3- benzoxazole MS m/z (M + H⁺) 542 1158 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-2-[3-(trifluoromethyl)phenyl]-1,3- benzoxazole MS m/z (M + H⁺) 542

Example 1e

Q. Ethyl 2-phenyl-benzothiazole-6-carboxylate, 1y

A mixture of ethyl 2-bromo-benzothiazole-6-carboxylate 1w (300 mg, 1.05 mmol), phenylboronic acid 1x (192 mg, 1.57 mmol), K₂CO₃ (188 mg, 1.36 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (43 mg, 0.05 mmol) in dioxane (2 mL) and H₂O (0.4 ml) was heated at 120° C. for 25 min under microwave. The reaction mixture was diluted with CH₂Cl₂, washed with H₂O, dried over Na₂SO₄, and concentrated. Purification by flash column chromatography (silica gel, 15% EtOAc/heptane) gave 1y (220 mg).

R. 2-Phenyl-benzothiazole-6-carboxylic acid, 1z

Ethyl 2-phenyl-benzothiazole-6-carboxylate 1y (220 mg, 0.78 mmol) was stirred with LiOH (74 mg, 3.1 mmol) in THF (4 mL) and H2O (4 mL) for 16 h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3˜4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na₂SO₄ and concentrated to give 1z (200 mg).

Following the procedure described above for Example 1e and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compound was prepared:

Following the procedure described above for Example 1, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 592 2-Phenyl-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1,3-benzothiazole MS m/z (M + H⁺) 483 1125 2-Phenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,3-benzothiazole ¹H NMR (400 MHz, CD₃OD): d 8.25 (s, 1H), 8.12-8.06 (m, 3H), 7.88 (d, J = 3 Hz, 1H), 7.74 (d, J = 8 Hz, 1H), 7.53 (m, 4H), 4.53 (bs, 1H), 4.4-4.26 (m, 4H), 4.15 (m, 1H), 3.86 (m, 2H), 3.27 (m, 1H), 2.50 (m, 4H) MS m/z (M + H⁺) 490 1187 2-Phenyl-6-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,3-benzothiazole MS m/z 490 (M + H⁺)

Example 1f

Q. Methyl 1-(5-chloropyridin-2-yl)-1H-indole-5-carboxylate, 1bb

A mixture of 1j (1.14 mmol, 200 mg), 1aa (1.14 mmol, 150 mg), K₂CO₃ (2.28 mmol, 315 mg) and NMP (1.5 mL) was heated at 200° C. in a microwave reactor for 2 h. The mixture was poured into water (50 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄ and concentrated under vacuo. Purification was carried by flash column chromatography (silica gel, 15% EtOAc/heptane) to give 290 mg of 1bb (290 mg).

R. (5-Chloropyridin-2-yl)-1H-indole-5-carboxylic acid, 1cc

A mixture of 1bb (0.942 mmol, 270 mg), LiOH (3.77 mmol, 90 mg), THF (3 mL), MeOH (3 mL), and H₂O (3 mL) was stirred at room temperature for overnight. The reaction mixture was acidified with 1N aqueous HCl to pH=5. The solid precipitate was filtered, washed with EtOAc, and dried under vacuo to give 202 mg of 1cc.

Following the procedure described above for Example 1, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1313 1-(5-Chloropyridin-2-yl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole ¹H NMR (CDCl₃) d: 8.52 (d, J = 2.2 Hz, 1H), 8.21 (d, J = 8.6 Hz, 1H), 7.96 (s, 1H), 7.88 (d, J = 3.2 Hz, 1H), 7.81 (dd, J = 8.6, 2.4 Hz, 1H), 7.70 (d, J = 3.4 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 2.9 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 6.77 (d, J = 3.4 Hz, 1H), 4.51 (br. s., 1H), 4.19-4.47 (m, 4H), 4.12 (q, J = 7.1 Hz, 2H), 3.74-3.95 (m, 2H), 3.25 (t, J = 5.6 Hz, 1H), 2.49 (br. s., 4H) MS m/z (M + H⁺) 508.0 629 1-(5-Chloropyridin-2-yl)-5-({3-[4- (phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)- 1H-indole MS m/z (M + H⁺) 501.0 1180 1-(5-Chloropyridin-2-yl)-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole ¹H NMR (CDCl₃) d: 8.79 (s, 1H), 8.49 (s, 1H), 8.21 (d, J = 8.6 Hz, 1H), 7.95 (s, 1H), 8.00 (s, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.68 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 6.75 (d, J = 2.9 Hz, 1H), 4.31-4.47 (m, 1H), 4.16-4.31 (m, 1H), 4.11 (q, J = 7.0 Hz, 1H), 3.84-4.04 (m, 3H), 3.80 (br. s., 1H), 3.18-3.31 (m, 1H), 2.47 (br. s., 3H), 2.40 (br. s., 1H) MS m/z (M + H⁺) 507.0

Example 2

A. [4-(1-Benzhydryl-azetidin-3-yl)-piperazin-1-yl]-phenyl-methanone, 2b

The title compound 2b was prepared using the method described in Example 1, substituting compound 2a for compound 1d in Procedure C. The crude compound 2b was purified by flash column chromatography. MS m/z (M+H⁺) 412.2.

B. (4-Azetidin-3-yl-piperazin-1-yl)-phenyl-methanone, 2c

The title compound 2c was prepared using the method described in Example 1, substituting compound 2b for compound 1f in Procedure D. The crude compound 2c was used in the next reaction without further purification. MS m/z (M+H⁺) 246.1.

C. 1-{1-[(4-Bromophenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine, Cpd 27

The title compound 27 was prepared using the method described in Example 1, substituting compound 2c for compound 1g and substituting compound 2d for compound 1h in Procedure E. The crude compound 27 was purified by reverse phase chromatography. MS m/z (M+H⁺) 428.1/430.0.

Following the procedure described above for Example 2 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 28 1-(Phenylcarbonyl)-4-(1-{[4-(1H-pyrrol-1- yl)phenyl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 415.2 29 1-(Phenylcarbonyl)-4-{1-[(4-pyrrolidin-1- ylphenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 419.2 30 N,N-Diethyl-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)aniline LC/MS m/z (M + H⁺) 421.2 31 N,N-Dimethyl-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)aniline MS m/z (M + H⁺) 393.2 32 1-{1-[(4-Phenoxyphenyl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 442.2 33 1-{1-[(4′-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 444.1 34 1-{1-[(4′-Methoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 456.1 35 1-(1-{[4-(Benzyloxy)phenyl]carbonyl}azetidin-3-yl)-4- (phenylcarbonyl)piperazine LC/MS (m/z) (M + H⁺) 456.1 36 1-{1-[(2′-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 460.2 37 1-Cyclohexyl-2-methyl-5-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole LC/MS m/z (M + H⁺) 486.3 38 1-(1-Methylethyl)-5-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-2-(trifluoromethyl)-1H-benzimidazole LC/MS m/z (M + H⁺) 500.3 39 1-{1-[(3′,4′-Dichlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.73 (d, 1H), 7.65 (m, 4H), 7.50 (m, 2H), 7.35-7.46 (m, 5H), 4.55 (m, 2H), 4.35 (m, 2H), 4.01 (m, 1H), 3.80 (m, 4H), 3.17 (m, 4H); LC/MS m/z (M + H⁺) 494.1 (calculated for C₂₇H₂₅Cl₂N₃O₂, 494.43) 40 N-Methyl-N-phenyl-4-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)aniline ¹H NMR (300 MHz, CD₃OD): δ 7.45-7.56 (m, 7H), 7.41 (t, 2H), 7.22 (m, 3H), 6.80 (d, 2H), 4.27-4.75 (m, 4H), 4.07 (m, 1H), 3.88 (m, 4H), 3.34 (s, 3H), 3.25 (m, 4H); LC/MS m/z (M + H⁺) 455.3 (calculated for C₂₈H₃₀N₄O₂, 454.58) 41 1-[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenyl]azepane ¹H NMR (300 MHz, CD₃OD): δ 7.45-7.57 (m, 7H), 6.73 (d, 2H), 4.28-4.73 (m, 4H), 4.12 (m, 1H), 3.89 (m, 4H), 3.30 (m, 8H), 1.80 (m, 4H), 1.54 (m, 4H); LC/MS m/z (M + H⁺) 447.3 (calculated for C₂₇H₃₄N₄O₂, 446.6) 42 5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1-propyl-1H-indole LC/MS m/z (M + H⁺) 431.1 43 1-(Biphenyl-4-ylcarbonyl)-2-phenyl-4-[1-(1,3-thiazol-2- ylcarbonyl)azetidin-3-yl]piperazine ¹H NMR (400 MHz, MeOD): δ 7.86-7.95 (m, 1H), 7.73-7.79 (m, 1H), 7.62-7.68 (m, 2H), 7.53-7.59 (m, 2H), 7.47-7.52 (m, 2H), 7.41-7.47 (m, 2H), 7.33-7.41 (m, 4H), 7.21-7.33 (m, 2H), 5.67 (br. s., 1H), 4.51-4.62 (m, 2H), 4.19-4.38 (m, 1H), 4.01-4.12 (m, 1H), 3.71-3.81 (m, 1H), 3.54-3.67 (m, 1H), 3.32 (m, 1H), 2.98-3.12 (m, 2H), 2.79-2.90 (m, 1H), 2.44-2.56 (m, 1H); MS m/z (M + H⁺) 509.2 (calculated for C₃₀H₂₈N₄O₂S, 508.65) 44 1-(Biphenyl-4-ylcarbonyl)-2-phenyl-4-[1- (phenylcarbonyl)azetidin-3-yl]piperazine ¹H NMR (400 MHz, MeOD): δ 7.67-7.75 (m, 2H), 7.59-7.67 (m, 4H), 7.53-7.58 (m, 2H), 7.40-7.53 (m, 9H), 7.31-7.40 (m, 2 H), 5.73 (br. s., 1 H), 4.34-4.57 (m, 1H), 4.23-4.34 (m, 1H), 4.02-4.18 (m, 2H), 3.69-3.88 (m, 1H), 3.55-3.68 (m, 1H), 3.35-3.46 (m, 2H), 3.07 (m, 1H), 2.81-2.93 (m, 1H), 2.43-2.63 (m, 1H); MS m/z (M⁺) 502.2 (calculated for C₃₃H₃₁N₃O₂, 502.23) 45 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-2-methyl-4-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 447.29 (calculated for C₂₅H₂₆N₄O₂S, 446.58) 46 2-Methyl-1-{1-[(4-phenoxyphenyl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 463.2 (calculated for C₂₅H₂₆N₄O₃S, 462.57) 47 1-{1-[(4-Benzylphenyl)carbonyl]azetidin-3-yl}-2-methyl-4-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 461.0 (calculated for C₂₆H₂₈N₄O₂S, 460.60) 48 1-[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenyl]-1H-benzimidazole MS m/z (M + H⁺) 466.3 (calculated for C₂₈H₂₇N₅O₂, 465.56) 49 1-{1-[(4-Fluorophenyl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 368.2 (calculated for C₂₁H₂₂FN₃O₂, 367.43) 50 N-Benzyl-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1,3-thiazol-2-amine MS m/z (M + H⁺) 462.2 (calculated for C₂₅H₂₇N₅O₂S, 461.59) 51 9-Methyl-3-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-9H-carbazole MS m/z (M + H⁺) 453.3 (calculated for C₂₈H₂₈N₄O₂, 452.56) 52 N-Benzyl-2-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)aniline MS m/z (M + H⁺) 455.3 (calculated for C₂₈H₃₀N₄O₂, 454.58) 53 1-(Phenylcarbonyl)-4-{1-[(4-piperidin-1- ylphenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 433.3 (calculated for C₂₆H₃₂N₄O₂, 432.57) 54 N-Butyl-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)aniline MS m/z (M + H⁺) 421.2 (calculated for C₂₅H₃₂N₄O₂, 420.56) 55 6-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-2,3,4,9-tetrahydro-1H-carbazole MS (m/z) (M + H⁺) 443.3 (calculated for C₂₇H₃₀N₄O₂, 442.57) 56 2-[3-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenyl]-2,3-dihydro-1H-isoindole MS m/z (M + H⁺) 467.2 (calculated for C₂₉H₃₀N₄O₂, 466.59) 57 2-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-N-[3-(trifluoromethyl)phenyl]aniline MS m/z (M + H⁺) 509.1 (calculated for C₂₈H₂₇F₃N₄O₂, 508.55) 58 N-Phenyl-2-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)aniline MS m/z (M + H⁺) 441.2 (calculated for C₂₇H₂₈N₄O₂, 440.55) 59 N-(3-Fluorophenyl)-2-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)aniline MS m/z (M + H⁺) 459.2 (calculated for C₂₇H₂₇FN₄O₂, 458.54) 60 2,3-Dimethyl-N-[2-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)phenyl]aniline MS m/z (M + H⁺) 469.2 (calculated for C₂₉H₃₂N₄O₂, 468.60) 461 1-(1-{[2-(Benzyloxy)phenyl]carbonyl}azetidin-3-yl)-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 456.221 462 1-{1-[(3-Phenoxyphenyl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 442.3 463 1-{1-[(2-Phenoxyphenyl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 442.3 464 1-(Phenylcarbonyl)-4-(1-{[4- (trifluoromethoxy)phenyl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 434.161 465 1-{1-[(3-Bromo-4-methoxyphenyl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 458.1 466 1-{1-[(3-Chloro-4-methoxyphenyl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 414.151 467 1-{1-[(4-Ethoxyphenyl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 394.205 468 1-{1-[(3-Iodo-4-methoxyphenyl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 506.086 469 1-(1-{[4-(1-Methylethoxy)phenyl]carbonyl}azetidin-3-yl)-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 408.221 470 1-(1-{[4-(Methylsulfanyl)phenyl]carbonyl}azetidin-3-yl)-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 396.167 471 4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenyl acetate MS m/z (M + H⁺) 415.136 472 1-(1-{[4-(Methylsulfonyl)phenyl]carbonyl}azetidin-3-yl)-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 428.157 539 N-[3-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenyl]cyclohexanecarboxamide MS m/z (M + H⁺) 475.2 622 1-(Phenylcarbonyl)-4-[1-({4-[3-(trifluoromethyl)-1H-pyrazol-1- yl]phenyl}carbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 484.0 531 N-Benzyl-3-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)aniline MS m/z (M + H⁺) 455.1 565 1-Benzyl-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)pyridin-2(1H)-one MS m/z (M + H⁺) 457.1 562 1-(3-Chlorobenzyl)-3-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)pyridin-2(1H)-one MS m/z (M + H⁺) 491.1 627 1-(Phenylcarbonyl)-4-(1-{[3-(1H-pyrrol-1- yl)phenyl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 415.2 541 4-[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenyl]morpholine MS m/z (M + H⁺) 435.1 1485 4-[5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)pyridin-2-yl]morpholine MS m/z (M + H⁺) 436.0 559 4-{1-[(4-Benzylphenyl)carbonyl]azetidin-3-yl}-2-phenyl-1- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 516.1 628 4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-2-phenyl-1- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 502.0 1404 4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-2-phenyl-1-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 509.1 1464 4-{1-[(4-Benzylphenyl)carbonyl]azetidin-3-yl}-2-phenyl-1-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 523.1 1266 2-Benzyl-1-(biphenyl-4-ylcarbonyl)-4-[1-(1,3-thiazol-2- ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 523.3 1284 2-Benzyl-1-(biphenyl-4-ylcarbonyl)-4-[1-(1,3-thiazol-4- ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 523.2 954 (2R,6S)-2,6-Dimethyl-1-(1,3-thiazol-2-ylcarbonyl)-4-(1-{[6- (trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3- yl)piperazine MS m/z (M + H⁺) 509.0

Example 3

A. (4-Benzyl-phenyl)-piperazin-1-yl-methanone, 3b

To a solution of compound 1a (1 g, 5.36 mmol), compound 3a (1.14 g, 5.36 mmol), and DIPEA (1.38 g, 10.7 mmol) in acetonitrile (20 mL) was added HBTU (2.64 g, 7.0 mmol). The reaction was stirred for 18 h at which time the solvent was removed under reduced pressure and the crude product purified by reverse phase HPLC. Upon lyophilization, the remaining solid was dissolved in DCM (20 mL) and trifluoroacetic acid was slowly added (15 mL). After stirring at room temperature 2 h, the solvents were removed and the residue partitioned between aqueous 1N NaOH and CHCl₃. The organic layer was separated, dried (MgSO₄), filtered, and then concentrated to yield compound 3b (1.21 g).

B. [4-(1-Benzhydryl-azetidin-3-yl)-piperazin-1-yl]-4-benzyl-phenyl-methanone, 3c

The title compound 3c was prepared using the method described in Example 1, substituting compound 3b for compound 1d in Procedure C.

C. (4-Azetidin-3-yl-piperazin-1-yl)-4-benzyl-phenyl-methanone, 3d

The title compound 3d was prepared using the method described in Example 1, substituting compound 3c for compound 1f in Procedure D.

D. 1-[(4-Benzylphenyl)carbonyl]-4-[1-(phenylcarbonyl)azetidin-3-yl]piperazine, Cpd 61

Compound 3d was converted into title compound 61 using the method described in Example 2, substituting compound 3d for compound 2c, benzoic acid (compound 1k) for compound 2d, and HBTU for HATU in Procedure D. ¹H NMR (400 MHz, MeOD): δ 7.64 (d, J=1.7 Hz, 2H), 7.51-7.58 (m, 1H), 7.48 (br. s., 2H), 7.38 (s, 2H), 7.33 (d, J=8.1 Hz, 2H), 7.25 (br. s., 2H), 7.20 (d, J=7.3 Hz, 3H), 4.51-4.64 (m, 1H), 4.33-4.51 (m, 2H), 4.20-4.33 (m, 1H), 4.01 (s, 2H), 3.86-3.96 (m, 2H), 3.69-3.86 (m, 3H), 3.07 (br. s., 4H); MS m/z (M+H⁺) 440.2 (calculated for C₂₈H₂₉N₃O₂, 439.56)

Following the procedure described above for Example 3 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1246 1-(Biphenyl-4-ylcarbonyl)-4-[1-(1,3-thiazol-4- ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 433.1 1235 1-(Biphenyl-4-ylcarbonyl)-4-[1-(isothiazol-5- ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 433.2 1242 1-(Biphenyl-4-ylcarbonyl)-4-{1-[(3- fluorophenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 444.1 1236 1-(Biphenyl-4-ylcarbonyl)-4-[1-(1,3-thiazol-2- ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 433.2 1383 1-(Biphenyl-4-ylcarbonyl)-4-[1-(1H-pyrrol-2- ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 414.0 1276 1-(Biphenyl-4-ylcarbonyl)-4-[1-(1,2,3-thiadiazol-4- ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 434.0 1292 1-(Biphenyl-4-ylcarbonyl)-4-[1-(1H-pyrrol-3- ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 413.0 1400 2-({3-[4-(Biphenyl-4-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)pyrimidine MS m/z (M + H⁺) 428.1 1283 1-(Biphenyl-4-ylcarbonyl)-4-[1-(1,3-oxazol-2- ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 417.0 676 1-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]-4-{[5- (trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}piperazine MS m/z (M + H⁺) 481.1 722 1-[1-(1H-Pyrrol-2-ylcarbonyl)azetidin-3-yl]-4-{[5- (trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}piperazine MS m/z (M + H⁺) 462.1 741 1-[1-(1H-Pyrrol-3-ylcarbonyl)azetidin-3-yl]-4-{[5- (trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}piperazine MS m/z (M + H⁺) 461.0 716 1-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]-4-{[5- (trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}piperazine MS m/z (M + H⁺) 481.0 703 1-[1-(Isothiazol-5-ylcarbonyl)azetidin-3-yl]-4-{[5- (trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}piperazine MS m/z (M + H⁺) 481.0 921 1-[1-(1,2,5-Oxadiazol-3-ylcarbonyl)azetidin-3-yl]-4-{[5- (trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}piperazine MS m/z (M + H⁺) 466.1 753 1-[1-(1,2,3-Thiadiazol-4-ylcarbonyl)azetidin-3-yl]-4-{[5- (trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}piperazine MS m/z (M + H⁺) 482.2 1067 1-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]-4-{[3′- (trifluoromethyl)biphenyl-4-yl]carbonyl}piperazine MS m/z (M + H⁺) 501.0 1243 1-[1-(1H-Pyrrol-3-ylcarbonyl)azetidin-3-yl]-4-{[3′- (trifluoromethyl)biphenyl-4-yl]carbonyl}piperazine MS m/z (M + H⁺) 483.0 1166 1-[1-(1H-Pyrrol-2-ylcarbonyl)azetidin-3-yl]-4-{[3′- (trifluoromethyl)biphenyl-4-yl]carbonyl}piperazine MS m/z (M + H⁺) 483.0 1402 4-(Biphenyl-4-ylcarbonyl)-2-phenyl-1-[1-(1,3-thiazol-4- ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 509.0 1401 4-(Biphenyl-4-ylcarbonyl)-2-phenyl-1-[1-(1,3-thiazol-2- ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 509.0

Example 4

A. 3-(4-Benzoyl-piperazin-1-yl)-azetidine-1-carboxylic acid tert-butyl ester, 4b

To a solution of 1-Boc-azetidin-3-one (compound 4a) and compound 2a in CH₃OH was added decaborane at room temperature. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure, and the crude compound 4b was used in the subsequent reaction without further purification. MS m/z (M+H⁺) 346.2.

B. (4-Azetidin-3-yl-piperazin-1-yl)-phenyl-methanone, 2c

The title compound 2c was prepared using the method described in Example 1, substituting compound 4b for compound 1c in Procedure B. The crude compound 2c was used in the next reaction without further purification. MS m/z (M+H⁺) 246.1.

C. 1-{1-[(4-Methyl-2-phenyl-1,3-thiazol-5-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine, Cpd 62

The title compound 62 was prepared using the method described in Example 1, substituting compound 2c for compound 1g and substituting compound 4c for compound 1h in Procedure E. The crude compound 62 was purified by reverse phase chromatography. MS m/z (M+H⁺) 447.1.

Following the procedure described above for Example 4 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 63 1-{1-[(4-Methyl-2-thiophen-2-yl-1,3-thiazol-5- yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 453.1 64 1-(1-{[4-Methyl-2-(4-methylphenyl)-1,3-thiazol-5- yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 461.2 65 1-[1-({4-Methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 515.1 66 1-(Phenylcarbonyl)-4-{1-[(3-thiophen-2- ylphenyl)carbonyl]azetidin-3-yl}piperazine LC/MS m/z (M + H⁺) 432.1 67 1-(Phenylcarbonyl)-4-{1-[(4-thiophen-2- ylphenyl)carbonyl]azetidin-3-yl}piperazine LC/MS m/z (M + H⁺) 432.1 68 1-(Phenylcarbonyl)-4-{1-[(3-pyridin-2- ylphenyl)carbonyl]azetidin-3-yl}piperazine LC/MS m/z (M + H⁺) 427.2 69 1-(Phenylcarbonyl)-4-{1-[(3-pyridin-3- ylphenyl)carbonyl]azetidin-3-yl}piperazine LC/MS m/z (M + H⁺) 427.2 70 1-(Phenylcarbonyl)-4-{1-[(3-pyridin-4- ylphenyl)carbonyl]azetidin-3-yl}piperazine LC/MS m/z (M + H⁺) 427.2 71 1-(Phenylcarbonyl)-4-{1-[(4-pyridin-3- ylphenyl)carbonyl]azetidin-3-yl}piperazine LC/MS m/z (M + H⁺) 427.2 72 1-(Phenylcarbonyl)-4-(1-{[2′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.81 (d, 1H), 7.64-7.77 (m, 3H), 7.59 (t, 1H), 7.42-7.54 (m, 7H), 7.36 (d, 1H), 4.70 (m, 1H), 4.58 (m, 1H), 4.47 (m, 1H), 4.35 (m, 1H), 4.04 (m, 1H), 3.86 (m, 4H), 3.19 (m, 4H); LC/MS m/z (M + H⁺) 494.2 (calculated for C₂₈H₂₆F₃N₃O₂, 493.53) 73 1-(Phenylcarbonyl)-4-(1-{[2′-(trifluoromethyl)biphenyl-3- yl]carbonyl}azetidin-3-yl)piperazine LC/MS m/z (M + H⁺) 494.2 74 1-(Phenylcarbonyl)-4-(1-{[4′-(trifluoromethyl)biphenyl-3- yl]carbonyl}azetidin-3-yl)piperazine LC/MS m/z (M + H⁺) 494.2 75 1-(Phenylcarbonyl)-4-(1-{[4′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.74-7.89 (m, 8H), 7.46-7.54 (m, 5H), 4.68 (m, 1H), 4.61 (m, 1H), 4.47 (m, 1H), 4.38 (m, 1H), 4.07 (m, 1H), 3.88 (m, 4H), 3.23 (m, 4H)); LC/MS m/z (M + H⁺) 494.2 (calculated for C₂₈H₂₆F₃N₃O₂, 493.53) 76 4′-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)biphenyl-3-carbonitrile LC/MS m/z (M + H⁺) 451.0 77 1-{1-[(3′-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine ¹H NMR (300 MHz, DMSO-d₆): δ 7.77-7.86 (m, 3H), 7.68-7.76 (m, 3H), 7.43-7.58 (m, 7H), 4.60 (m, 2H), 4.39 (m, 1H), 4.28 (m, 1H), 4.08 (m, 1H), 3.29-3.94 (m, 6H), 3.06 (m, 2H); LC/MS m/z (M + H⁺) 460.0 (calculated for C₂₇H₂₆ClN₃O₂, 459.98) 78 1-{1-[(4′-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 460.0 79 1-{1-[(3′,5′-Dichlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine ¹H NMR (300 MHz, DMSO-d₆): δ 7.87 (d, 2H), 7.81 (d, 2H), 7.73 (d, 2H), 7.67 (t, 1H), 7.48 (m, 5H), 4.67 (m, 1H), 4.58 (t, 1H), 4.43 (m, 1H), 4.29 (t, 1H), 4.10 (m, 1H), 3.25-3.93 (m, 6H), 3.06 (m, 2H); LC/MS m/z (M + H⁺) 494.1 (calculated for C₂₇H₂₅Cl₂N₃O₂, 494.43) 80 1-(Phenylcarbonyl)-4-{1-[(5-phenylpyridin-3- yl)carbonyl]azetidin-3-yl}piperazine LC/MS m/z (M + H⁺) 427.2 81 1-{1-[(2-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 444.1 82 4′-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)biphenyl-4-carbonitrile LC/MS m/z (M + H⁺) 451.2 83 1-{1-[(4′-Bromobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.25-7.74 (m, 13H), 4.08-4.59 (m, 4H), 3.43-3.97 (m, 5H), 2.92 (m, 4H); LC/MS m/z (M + H⁺) 504.0/506.1 (calculated for C₂₇H₂₆BrN₃O₂, 504.43) 474 1-(1-{[2-(4-Chlorophenoxy)pyridin-3-yl]carbonyl}azetidin- 3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 477.2 473 1-{1-[3-(4-Methylphenyl)propanoyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 392.3 84 1-{1-[3-(4-Chlorophenyl)propanoyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 412.21 (calculated for C₂₃H₂₆ClN₃O₂, 411.92) 85 1-{1-[3-(4-Bromophenyl)propanoyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 456.15 (calculated for C₂₃H₂₆BrN₃O₂, 456.38) 86 1-(Phenylcarbonyl)-4-(1-{3-[4- (trifluoromethyl)phenyl]propanoyl}azetidin-3-yl)piperazine LC/MS m/z (M + H⁺) 446.23 (calculated for C₂₄H₂₆F₃N₃O₂, 445.48) 87 1-{1-[3-(3-Chlorophenyl)propanoyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 412.18 (calculated for C₂₃H₂₆ClN₃O₂, 411.92) 88 1-{1-[3-(2-Chlorophenyl)propanoyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 412.21 (calculated for C₂₃H₂₆ClN₃O₂, 411.92) 89 1-{1-[3-(2,6-Dichlorophenyl)propanoyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 446.16 (calculated for C₂₃H₂₅Cl₂N₃O₂, 446.37) 90 1-{1-[3-(1,3-Benzodioxol-5-yl)propanoyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 422.2 (calculated for C₂₄H₂₇N₃O₄, 421.49) 91 1-(Phenylcarbonyl)-4-{1-[(2E)-3-{4- [(trifluoromethyl)sulfanyl]phenyl}prop-2-enoyl]azetidin-3- yl}piperazine LC/MS m/z (M + H⁺) 476.20 (calculated for C₂₄H₂₄F₃N₃O₂S, 475.54 92 1-(1-{3-[3,5-Bis(trifluoromethyl)phenyl]propanoyl}azetidin- 3-yl)-4-(phenylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 514.18 (calculated for C₂₅H₂₅F₆N₃O₂, 514.18) 93 1-[1-(3-Naphthalen-1-ylpropanoyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 428.27 (calculated for C₂₇H₂₉N₃O₂, 427.54) 94 1-{1-[3-(3,4-Dichlorophenyl)propanoyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 448.16 (calculated for C₂₃H₂₅Cl₂N₃O₂, 446.38) 95 1-{1-[3-(4-Phenoxyphenyl)propanoyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 470.29 (calculated for C₂₉H₃₁N₃O₃, 469.59) 96 1-{1-[(4-Chlorophenoxy)acetyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 414.21 (calculated for C₂₂H₂₄ClN₃O₃, 413.91) 97 1-(Phenylcarbonyl)-4-{1-[3-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)propanoyl]azetidin-3- yl}piperazine. LC/MS m/z (M + H⁺) 488.32 (calculated for C₃₁H₄₁N₃O₂, 487.69) 98 1-{1-[3-(2-Bromophenyl)propanoyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 458.18 (calculated for C₂₃H₂₆BrN₃O₂, 456.39 99 1-(Phenylcarbonyl)-4-(1-{[4- (trifluoromethoxy)phenoxy]acetyl}azetidin-3-yl)piperazine. LC/MS m/z (M + H⁺) 464.26 (calculated for C₂₃H₂₄F₃N₃O₄, 475.54 100 N-Cyclopropyl-4-(3-oxo-3-{3-[4-(phenylcarbonyl)piperazin- 1-yl]azetidin-1-yl}propyl)benzenesulfonamide. LC/MS m/z (M + H⁺) 497.23 (calculated for C₂₆H₃₂N₄O₄S, 496.21 101 N-(Cyclohexylmethyl)-N-methyl-4-(3-oxo-3-{3-[4- (phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}propyl)aniline. LC/MS m/z (M + H⁺) 503.37 (calculated for C₃₁H₄₂N₄O₂, 502.71 102 1-[1-(1-Benzothiophen-2-ylcarbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 406.2 (calculated for C₂₃H₂₃N₃O₂S, 405.52 103 1-{1-[(2E)-3-(2-Chlorophenyl)prop-2-enoyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 410.29 (calculated for C₂₃H₂₄ClN₃O₂, 409.92 104 1-{1-[(2E)-3-(2-Bromophenyl)prop-2-enoyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 456.16 (calculated for C₂₃H₂₄BrN₃O₂, 454.37 105 1-{1-[(2E)-3-Naphthalen-2-ylprop-2-enoyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 426.32 (calculated for C₂₇H₂₇N₃O₂, 425.54 106 1-(Phenylcarbonyl)-4-{1-[(4- phenylcyclohexyl)carbonyl]azetidin-3-yl}piperazine. LC/MS m/z (M + H⁺) 432.38 (calculated for C₂₇H₃₃N₃O₂, 431.58 107 3-Methyl-2-phenyl-8-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-4H-chromen-4-one. LC/MS m/z (M + H⁺) 508.31 (calculated for C₃₁H₂₉N₃O₄, 507.59 108 Phenyl[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)cyclohexyl]methanone. LC/MS m/z (M + H⁺) 460.35 (calculated for C₂₈H₃₃N₃O₃, 459.59) 109 tert-Butyl 4-[4-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)phenyl]piperidine-1-carboxylate. ¹H NMR (300 MHz, MeOD): δ 7.55 (Ar, 2H), 7.4 (m, 5H). 7.25 (ar, 2H), 4.5 (m, 2H), 4.3 (m, 2H), 4.1 (m, 3H), 3.7 (bm, 4H), 3.0 (bm, 4H), 2.7 (m, 4H), 1.7 (m, 2H), 1.5 (m, 2H), 1.4 (s, 9H). LC/MS m/z (M + H⁺) 533.33 (calculated for C₃₁H₄₀N₄O₄, 532.69 110 1-{1-[(2-Phenoxypyridin-3-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 443.28 (calculated for C₂₆H₂₆N₄O₃, 442.52 111 tert-Butyl 3-[2-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)phenyl]pyrrolidine-1-carboxylate. LC/MS m/z (M + H⁺) 519.35 (calculated for C₃₀H₃₈N₄O₄, 518.66) 496 tert-Butyl [4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)phenyl]carbamate ¹H NMR (400 MHz, CDCl₃): δ 7.57 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.36-7.42 (m, 4H), 7.20 (s, 1H), 4.25-4.34 (m, 1H), 4.17-4.26 (m, 1H), 4.13 (s, 1H), 3.97-4.08 (m, 1H), 3.81-3.95 (m, 1H), 3.68-3.80 (m, 1H), 3.32-3.61 (m, 2H), 3.15-3.27 (m, 1H), 2.16-2.59 (m, 4H), 1.50 (s, 9H) MS (m/z) (M + H⁺) 465.2 619 1-(1-{[2-(4-Chlorophenyl)-4-methyl-1,3-thiazol-5- yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 481.0 618 1-[1-({4-Methyl-2-[3-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 515.1 620 1-(1-{[2-(3-Chlorophenyl)-4-methyl-1,3-thiazol-5- yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 481.0 621 1-(1-{[2-(4-Fluorophenyl)-4-methyl-1,3-thiazol-5- yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 465.1 625 1-(Phenylcarbonyl)-4-(1-{[2-phenyl-5-(trifluoromethyl)-1,3- oxazol-4-yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 485.1 623 1-{1-[(2-Methyl-5-phenylfuran-3-yl)carbonyl]azetidin-3-yl}- 4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 430.2 624 1-(Phenylcarbonyl)-4-(1-{[5-phenyl-2- (trifluoromethyl)furan-3-yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 484.0 558 1-[1-({2-[(4-Chlorophenoxy)methyl]-4-methyl-1,3-thiazol-5- yl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 511.1 626 1-(Phenylcarbonyl)-4-(1-{[1-phenyl-5-(trifluoromethyl)-1H- pyrazol-4-yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 484.2

Example 5

A. 4-(1-Benzhydryl-azetidin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester, 5a

The title compound 5a was prepared using the method described in Example 1, substituting compound 1a for compound 1d in Procedure C. The crude compound 5a was used in the next reaction without further purification. MS m/z (M+H⁺) 408.1.

B. 1-(1-Benzhydryl-azetidin-3-yl)-piperazine, 5b

The title compound 5b was prepared using the method described in Example 1, substituting compound 5a for compound 1c in Procedure B. The crude compound 5b was used in the next reaction without further purification. MS m/z (M+H⁺) 208.1.

C. [4-(1-Benzhydryl-azetidin-3-yl)-piperazin-1-yl]-thiazol-2-yl-methanone, 5d

The title compound 5d was prepared using the method described in Example 1, substituting compound 5b for compound 1g and substituting compound 5c for compound 1h in Procedure E. The crude compound 5d was purified by flash column chromatography. MS m/z (M+H⁺) 419.2.

D. (4-Azetidin-3-yl-piperazin-1-yl)-thiazol-2-yl-methanone, 5e

The title compound 5e was prepared using the method described in Example 1, substituting compound 5d for compound 1f in Procedure D. The crude compound 5e was used in the next reaction without further purification. MS m/z (M+H⁺) 253.2.

E. 1-{1-[(4-Methyl-2-phenyl-1,3-thiazol-5-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 133

The title compound 133 was prepared using the method described in Example 1, substituting compound 5e for compound 1g and substituting compound 4c for compound 1h in Procedure E. The crude compound 133 was purified by reverse phase chromatography. ¹H NMR (300 MHz, CD₃OD): δ 7.98 (m, 3H), 7.89 (d, 1H), 7.46-7.55 (m, 3H), 4.80 (m, 1H), 4.41-4.69 (m, 4H), 4.09 (m, 3H), 3.35 (m, 5H), 2.68 (s, 3H); LC/MS m/z (M+H⁺) 454.2 (calculated for C₂₂H₂₃N₅O₂S₂, 453.59).

Following the procedure described above for Example 5 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 134 1-{1-[(4-Methyl-2-thiophen-2-yl-1,3-thiazol-5- yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.98 (s, 1H), 7.88 (s, 1H), 7.67 (m, 2H), 7.16 (m, 1H), 4.79 (m, 1H), 4.35-4.69 (m, 4H), 4.07 (m, 3H), 3.33 (m, 5H), 2.62 (s, 3H); LC/MS m/z (M + H⁺) 460.0 (calculated for C₂₀H₂₁N₅O₂S₃, 459.61) 135 1-(1-{[4-Methyl-2-(4-methylphenyl)-1,3-thiazol-5- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.98 (d, 1H), 7.82-7.91 (m, 3H), 7.32 (d, 2H), 4.80 (m, 1H), 4.40-4.66 (m, 4H), 4.08 (m, 3H), 3.34 (m, 5H), 2.66 (s, 3H), 2.46 (s, 3H); LC/MS m/z (M + H⁺) 468.1 (calculated for C₂₃H₂₅N₅O₂S₂, 467.62) 136 1-[1-({4-Methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 8.19 (d, 2H), 7.97 (d, 1H), 7.86 (d, 1H), 7.82 (d, 2H), 4.25-4.76 (m, 5H), 3.95 (m, 2H), 3.76 (m, 1H), 3.33 (m, 2H), 2.99 (m, 3H), 2.69 (s, 3H); LC/MS m/z (M + H⁺) 522.2 (calculated for C₂₃H₂₂F₃N₅O₂S₂, 521.59) 137 1-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(3-thiophen-2- ylphenyl)carbonyl]azetidin-3-yl}piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.91 (t, 1H), 7.88 (d, 1H), 7.83 (dt, 1H), 7.54 (m, 2H), 7.47 (dd, 2H), 7.13 (dd, 1H), 4.30-4.79 (m, 5H), 4.02 (m, 3H), 3.24 (m, 5H); LC/MS m/z (M + H⁺) 439.0 (calculated for C₂₂H₂₂N₄O₂S₂, 438.57) 138 1-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(4-thiophen-2- ylphenyl)carbonyl]azetidin-3-yl}piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.89 (d, 1H), 7.75 (m, 4H), 7.51 (m, 2H), 7.14 (m, 1H), 4.28-4.82 (m, 5H), 4.02 (m, 3H), 3.25 (m, 5H); LC/MS m/z (M + H⁺) 439.1 (calculated for C₂₂H₂₂N₄O₂S₂, 438.57) 139 1-{1-[(3-Pyridin-2-ylphenyl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 434.0 140 1-{1-[(3-Pyridin-3-ylphenyl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 434.0 141 1-{1-[(3-Pyridin-4-ylphenyl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 434.0 142 1-{1-[(4-Pyridin-3-ylphenyl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 434.0 143 5-[3-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenyl]pyrimidine LC/MS m/z (M + H⁺) 435.0 144 5-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenyl]pyrimidine LC/MS m/z (M + H⁺) 435.0 145 2-[3-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenyl]pyrimidine LC/MS m/z (M + H⁺) 435.0 146 2-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenyl]pyrimidine LC/MS m/z (M + H⁺) 435.0 147 1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[2′- (trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.88 (d, 1H), 7.81 (d, 1H), 7.74 (d, 2H), 7.68 (t, 1H), 7.59 (t, 1H), 7.45 (d, 2H), 7.37 (d, 1H), 4.33-4.82 (m, 5H), 4.04 (m, 3H), 3.27 (m, 5H); LC/MS m/z (M + H⁺) 501.0 (calculated for C₂₅H₂₃F₃N₄O₂S, 500.55) 148 1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[2′- (trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3- yl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.88 (d, 1H), 7.81 (d, 1H), 7.73 (dt, 1H), 7.67 (d, 1H), 7.49-7.64 (m, 4H), 7.39 (d, 1H), 4.30-4.81 (m, 5H), 4.03 (m, 3H), 3.25 (m, 5H); LC/MS m/z (M + H⁺) 501.0 (calculated for C₂₅H₂₃F₃N₄O₂S, 500.55) 149 1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[4′- (trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3- yl)piperazine LC/MS m/z (M + H⁺) 501.0 150 1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[4′- (trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.76-7.89 (m, 9H), 4.62-4.77 (m, 5H), 3.97 (m, 3H), 3.13 (m, 5H); LC/MS m/z (M + H⁺) 501.0 (calculated for C₂₅H₂₃F₃N₄O₂S, 500.55) 151 1-(1-{[3-(6-Bromopyridin-2-yl)phenyl]carbonyl}azetidin-3-yl)- 4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 8.34 (t, 1H), 8.21 (dt, 1H), 7.97 (d, 1H), 7.94 (dd, 1H), 7.87 (d, 1H), 7.72-7.82 (m, 2H), 7.54-7.67 (m, 2H), 4.26-4.68 (m, 6H), 3.84-4.06 (m, 3H), 3.13 (m, 4H); LC/MS m/z (M + H⁺) 512.0/513.9 (calculated for C₂₃H₂₂BrN₅O₂S, 512.43) 152 1-(1-{[3-(5-Nitropyridin-2-yl)phenyl]carbonyl}azetidin-3-yl)-4- (1,3-thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 479.0 153 1-(1-{[4-(5-Nitropyridin-2-yl)phenyl]carbonyl}azetidin-3-yl)-4- (1,3-thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 479.0 154 1-(1-{[5-(4-Fluorophenyl)pyridin-2-yl]carbonyl}azetidin-3-yl)- 4-(1,3-thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 452.0 155 1-(1-{[2-(4-Fluorophenyl)-1,3-thiazol-4-yl]carbonyl}azetidin-3- yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 458.0 156 1-(1-{[2-(3-Fluorophenyl)-1,3-thiazol-4-yl]carbonyl}azetidin-3- yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 458.0 157 1-(1-{[2-(2,4-Dichlorophenyl)-1,3-thiazol-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 507.9 158 1-(1-{[2-(3,5-Dichlorophenyl)-1,3-thiazol-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 8.31 (s, 1H), 7.89 (m, 3H), 7.79 (d, 1H), 7.52 (t, 1H), 5.01 (m, 1H), 4.84 (m, 2H), 4.65 (m, 1H), 4.38 (dd, 1H), 4.26 (dd, 1H), 3.93 (m, 3H), 3.17 (m, 4H); LC/MS m/z (M + H⁺) 507.9 (calculated for C₂₁H₁₉Cl₂N₅O₂S₂, 508.45) 159 1-(1-{[2-(4-Methoxyphenyl)-1,3-thiazol-4-yl]carbonyl}azetidin- 3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 470.0 160 1-{1-[(2-Phenyl-1,3-thiazol-4-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 440.0 161 4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)biphenyl-3-carbonitrile ¹H NMR (300 MHz, DMSO-d₆): δ 8.10 (d, 1H), 8.06 (d, 1H), 7.78-7.86 (m, 3H), 7.68-7.77 (m, 3H), 7.46-7.58 (m, 2H), 4.62 (m, 2H), 4.40 (m, 1H), 4.30 (m, 1H), 4.08 (m, 1H), 4.27-3.87 (m, 6H), 3.12 (m, 2H); LC/MS m/z (M + H⁺) 458.1 (calculated for C₂₅H₂₃N₅O₂S, 457.56) 162 1-{1-[(3′-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, DMSO-d₆): δ 8.10 (d, 1H), 8.06 (d, 1H), 7.78-7.86 (m, 3H), 7.68-7.77 (m, 3H), 7.46-7.58 (m, 2H), 4.61 (m, 2H), 4.37 (m, 1H), 4.29 (m, 1H), 4.05 (m, 1H), 4.30-3.84 (m, 6H), 3.08 (m, 2H); LC/MS m/z (M + H⁺) 467.1 (calculated for C₂₄H₂₃ClN₄O₂S, 466.99) 163 1-{1-[(4′-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.98 (d, 1H), 7.88 (d, 1H), 7.76 (m, 4H), 7.66 (m, 2H), 7.48 (m, 2H), 4.71 (m, 3H), 4.58 (m, 1H), 4.47 (m, 1H), 4.36 (m, 1H), 4.02 (m, 3H), 3.23 (m, 4H); LC/MS m/z (M + H⁺) 467.1 (calculated for C₂₄H₂₃ClN₄O₂S, 466.99) 164 1-{1-[(3′,5′-Dichlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.88 (d, 1H), 7.78 (d, 1H), 7.68 (m, 4H), 7.55 (d, 2H), 7.39 (t, 1H), 4.57 (m, 3H), 4.45 (m, 1H), 4.35 (m, 1H), 4.23 (m, 1H), 3.91 (m, 2H), 3.81 (m, 1H), 3.03 (m, 4H); LC/MS m/z (M + H⁺) 501.0 (calculated for C₂₄H₂₂Cl₂N₄O₂S, 501.44) 165 1-{1-[(5-Phenylpyridin-3-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 434.1 166 1-{1-[(2-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.87 (d, 1H), 7.37-7.67 (m, 8H), 4.66 (m, 3H), 4.53 (m, 1H), 4.42 (m, 1H), 4.30 (m, 1H), 3.98 (m, 2H), 3.85 (m, 1H), 3.07 (m, 4H); LC/MS m/z (M + H⁺) 451.0 (calculated for C₂₄H₂₃FN₄O₂S, 450.54) 167 4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)biphenyl-4-carbonitrile ¹H NMR (300 MHz, CD₃OD): δ 7.98 (d, 1H), 7.77-7.92 (m, 9 H), 4.63-4.79 (m, 3H), 4.57 (m, 1H), 4.46 (m, 1H), 4.35 (m, 1H), 3.90-4.13 (m, 3 H), 3.19 (m, 4 H); LC/MS m/z (M + H⁺) 458.1 (calculated for C₂₅H₂₃N₅O₂S, 457.56) 168 1-{1-[(4′-Bromobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.87 (d, 1H), 7.76 (m, 4H), 7.62 (dd, 4H), 4.67 (m, 3H), 4.51 (m, 1H), 4.44 (m, 1H), 4.30 (m, 1H), 3.98 (m, 2H), 3.88 (m, 1H), 3.10 (m, 4H); LC/MS m/z (M + H⁺) 511.0/513.0 (calculated for C₂₄H₂₃BrN₄O₂S, 511.44) 169 1-{1-[(5-Phenylpyridin-3-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-4-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 434.1 170 1-{1-[(2-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-4-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.22 (s, 1H), 7.37-7.67 (m, 8H), 4.70 (m, 1H), 4.57 (m, 1H), 4.45 (m, 1H), 4.34 (m, 1H), 4.11 (m, 4H), 3.99 (m, 1H), 3.17 (m, 4H); LC/MS m/z (M + H⁺) 451.0 (calculated for C₂₄H₂₃FN₄O₂S, 450.54) 171 4′-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)biphenyl-4-carbonitrile LC/MS m/z (M + H⁺) 458.1 172 1-{1-[(4′-Bromobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-4-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.22 (s, 1H), 7.76 (m, 4H), 7.61 (dd, 4H), 4.68 (m, 1H), 4.57 (m, 1H), 4.46 (m, 1H), 4.36 (m, 1H), 4.15 (m, 4H), 4.04 (m, 1H), 3.22 (m, 4H); LC/MS m/z (M + H⁺) 511.0/513.0 (calculated for C₂₄H₂₃BrN₄O₂S, 511.44) 475 1-{1-[(4-Phenylcyclohexyl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 439.2 476 3-Methyl-2-phenyl-8-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)-4H-chromen-4-one MS m/z (M + H⁺) 515.2 477 1-[1-(3-Phenylprop-2-ynoyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 381.1 478 Phenyl-[4-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)cyclohexyl]methanone MS m/z (M + H⁺) 467.2 479 1-[1-({2-[(4-Methylphenyl)sulfanyl]pyridin-3- yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 480.1 298 1-(1-{[5-(4-Methylphenyl)-1H-pyrrol-2-yl]carbonyl}azetidin-3- yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 436.2 112 2-Methyl-4-{1-[(4-phenoxyphenyl)carbonyl]azetidin-3-yl}-1- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 463.2 (calculated for C₂₅H₂₆N₄O₃S, 462.57) 113 2-Methyl-4-{1-[(3-phenoxyphenyl)carbonyl]azetidin-3-yl}-1- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 463.2 (calculated for C₂₅H₂₆N₄O₃S, 462.57) 114 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-2-phenyl-4-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 509.0 (calculated for C₃₀H₂₈N₄O₂S, 508.65) 115 4-{1-[(4-Benzylphenyl)carbonyl]azetidin-3-yl}-2-methyl-1-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 461.0 (calculated for C₂₆H₂₈N₄O₂S, 460.60) 116 4-[1-(Biphenyl-3-ylcarbonyl)azetidin-3-yl]-2-methyl-1-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 446.9 (calculated for C₂₅H₂₆N₄O₂S, 446.58) 117 4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-2-methyl-1-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H+) 447.3 (calculated for C₂₅H₂₆N₄O₂S, 446.58) 489 1-(1-{[2-(4-Chlorophenyl)-4-methyl-1,3-thiazol-5- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.81-8.02 (m, 4H), 7.52 (d, 2H), 4.30-4.64 (m, 6H) 3.84-4.09 (m, 3H), 3.10-3.29 (m, 4H), 2.67 (s, 3H); LC/MS m/z (M + H⁺) 488.1 (calculated for C₂₂H₂₂ClN₅O₂S₂, 488.03) 490 1-(1-{[2-(3-Chlorophenyl)-4-methyl-1,3-thiazol-5- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.95-8.05 (m, 2H), 7.84-7.94 (m, 2H), 7.45-7.60 (m, 2H), 4.32-4.84 (m, 6H) 3.92-4.09 (m, 3H), 3.15-3.27 (m, 4H), 2.68 (s, 3H); LC/MS m/z (M + H⁺) 488.1 (calculated for C₂₂H₂₂ClN₅O₂S₂, 488.03) 485 1-[1-({4-Methyl-2-[3-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.16-8.36 (m, 3H), 7.79-7.89 (m, 1H), 7.66-7.78 (m, 1H), 4.23-4.76 (m, 4H) 3.84-4.22 (m, 5H), 3.04-3.22 (m, 4H), 2.70 (s, 3H); LC/MS m/z (M + H⁺) 522.2 (calculated for C₂₃H₂₂F₂N₅O₂S₂, 521.59) 744 2,3-Dimethyl-N-[2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)phenyl]aniline MS m/z (M + H⁺) 476.1 1297 1-{1-[(1,5-Diphenyl-1H-pyrazol-4-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 499.1 768 2-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-N-[3-(trifluoromethyl)phenyl]aniline MS m/z (M + H⁺) 516.2 781 N-Phenyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)aniline MS m/z (M + H⁺) 448.0 1460 N-(3-Bromophenyl)-2-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)benzamide MS m/z (M + H⁺) 552.0/554.0 1214 1-(1-{[5-Methyl-2-(4-methylphenyl)-2H-1,2,3-triazol-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 452.1 754 N-(3-Fluorophenyl)-2-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline MS m/z (M + H⁺) 466.0 1103 1-(1-{[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H- pyrazol-3-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 615.0 886 1-[1-(Phenoxathiin-2-ylcarbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 479.1 1301 1-(1-{[1-(4-Fluorophenyl)-3,5-dimethyl-1H-pyrazol-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 469.1 1164 1-{1-[(1,5-Diphenyl-1H-pyrazol-3-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 499.1 1218 1-(1-{[2-(4-Chlorophenyl)-5-methyl-2H-1,2,3-triazol-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 472.1 843 4-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenyl]thiomorpholine 1,1-dioxide MS m/z (M + H⁺) 490.0 815 4-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenyl]morpholine MS m/z (M + H⁺) 442.0 1249 1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[3-(trifluoromethyl)-1H- pyrazol-1-yl]phenyl}carbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 491.1 1300 1-{1-[(2-Phenyl-2H-1,2,3-triazol-4-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 424.0 646 4-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)piperidin-1-yl]benzonitrile MS m/z (M + H⁺) 465.1 763 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-2,3,4,9-tetrahydro-1H-carbazole MS m/z (M + H⁺) 450.1 750 9-Methyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-9H-carbazole MS m/z (M + H⁺) 460.2 795 N-Benzyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,3-thiazol-2-amine MS m/z (M + H⁺) 469.0 1225 1-(1-{[1-(3,4-Dichlorophenyl)-3,5-dimethyl-1H-pyrazol-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 519.0 636 1-(1-Hexadecanoylazetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 491.4 687 1-Propyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 438.3 776 1-{1-[(3,5-Di-tert-butylphenyl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 469.4 637 1-(1-{[4-(4-Chlorophenyl)cyclohexyl]carbonyl}azetidin-3-yl)-4- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 473.2 672 1-{1-[(4-tert-Butylphenyl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 413.3 669 1-{1-[(4-Pyrrolidin-1-ylphenyl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 426.3 887 1-(1-{[4-(1,1-Dimethylpropyl)phenyl]carbonyl}azetidin-3-yl)-4- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 427.2 1434 1-[1-(4-Phenylbutanoyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 399.3 888 1-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenyl]azepane MS m/z (M + H⁺) 454.4 889 1-{1-[(4-Cyclohexylphenyl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 439.2 890 1-{1-[(1-Chloronaphtho[2,1-b]thiophen-2-yl)carbonyl]azetidin- 3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 497.1 891 1-(1-{[4-(2-Methylpropyl)phenyl]carbonyl}azetidin-3-yl)-4- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 413.3 892 1-{1-[(4-Heptylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 455.3 893 1-{1-[(4-Pentylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 427.2 655 1-{1-[(4-Propylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 399.1 894 1-{1-[(4-Butylphenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 413.3 849 1-{1-[(5-tert-Butyl-2-methoxyphenyl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 443.2 639 1-{1-[(5Z,8Z,11Z,14Z)-Icosa-5,8,11,14-tetraenoyl]azetidin-3- yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 539.4 641 1-{1-[(9Z)-Octadec-9-enoyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 517.3 638 1-{1-[(9Z,12Z)-Octadeca-9,12-dienoyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 515.4 1017 Phenyl[4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)phenyl]methanone MS m/z (M + H⁺) 461.1 1082 1-[1-({4-[4-(4-Fluorophenyl)-1,3-thiazol-2- yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 534.2 1245 1-[1-({4-[5-(4-Methylphenyl)-1H-1,2,3-triazol-1- yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 500.1 1326 1-(1-{[4-(4-Phenyl-1,3-thiazol-2-yl)phenyl]carbonyl}azetidin-3- yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 516.2 1327 3-(4-Chlorophenyl)-2-[4-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]- 4,5,6,7-tetrahydro-2H-indazole MS m/z (M + H⁺) 587.3 1179 1-(1-{[4-(4,5-Diphenyl-1H-imidazol-2- yl)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 575.2 693 1-(1-{[3-Chloro-4-(trifluoromethoxy)phenyl]carbonyl}azetidin- 3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 475.0 667 4-(3-Chlorophenyl)-8-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-3a,4,5,9b- tetrahydro-3H-cyclopenta[c]quinoline MS m/z (M + H⁺) 560.2 1328 1-[1-({4-[4-(2-Chlorophenyl)-1,3-thiazol-2- yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 550.0 1329 1-[1-({4-[4-(2,4-Dichlorophenyl)-1,3-thiazol-2- yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 584.1 640 1-(1-Icosanoylazetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 547.3 1156 1-[1-({4-[5-(4-Methylphenyl)-1,3,4-oxadiazol-2- yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 515.2 1330 2-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenyl]-3-[3-(trifluoromethyl)phenyl]-2,4,5,6- tetrahydrocyclopenta[c]pyrazole MS m/z (M + H⁺) 607.3 826 7-Chloro-2-methyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)quinoline MS m/z (M + H⁺) 456.1 797 6-Chloro-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)quinoline MS m/z (M + H⁺) 442.2 787 7-Chloro-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)quinoline MS m/z (M + H⁺) 442.2 835 6-Chloro-2-methyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)quinoline MS m/z (M + H⁺) 456.1 743 6,7-Dichloro-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)quinoline MS m/z (M + H⁺) 476.1 1331 1-[1-({4-[4-(3,4-Dichlorophenyl)-1,3-thiazol-2- yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 584.1 727 1-{1-[(4-Bromo-3-methylphenyl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 447.1/449.1 786 1-{1-[(4-Bromo-2-methylphenyl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 447.1/449.1 766 1-{1-[(2,2-Dimethyl-2,3-dihydro-1-benzofuran-5- yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 427.2 658 N,N-Dipropyl-4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)benzenesulfonamide MS m/z (M + H⁺) 520.2 816 N-Ethyl-2-[4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)phenoxy]acetamide MS m/z (M + H⁺) 458.3 874 Phenyl[5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-pyrrol-3-yl]methanone MS m/z (M + H⁺) 450.1 1332 1-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(4-{4-[3- (trifluoromethyl)phenyl]-1,3-thiazol-2- yl}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 584.1 1333 2-Phenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 472.2 1083 1-(1-{[5-(4-Chlorophenyl)-1-(3,4-dichlorophenyl)-1H-pyrazol- 3-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 601.0 788 1-(1-{[2,5-Dimethyl-1-(2,2,2-trifluoroethyl)-1H-pyrrol-3- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 456.1 702 2-Chloro-5-fluoro-N-[4-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenyl]benzamide MS m/z (M + H⁺) 529.0 770 1-[1-(3,4-Dihydro-2H-1,5-benzodioxepin-7-ylcarbonyl)azetidin- 3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 429.1 783 2-Methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,3-benzothiazole MS m/z (M + H⁺) 428.1 694 1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[(2,2,2- trifluoroethoxy)methyl]phenyl}carbonyl)azetidin-3- yl]piperazine MS m/z (M + H⁺) 469.2 836 N-{2-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)phenoxy]ethyl}acetamide MS m/z (M + H⁺) 458.3 730 1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[4-(2,2,2- trifluoroethoxy)phenyl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 455.1 1334 1-[1-({4-[4-(4-Chlorophenyl)-1H-pyrazol-1- yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 533.1 1203 1-(4-Fluorophenyl)-3-methyl-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- pyrazolo[3,4-b]pyridine MS m/z (M + H⁺) 506.2 1146 3-Methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1-[3-(trifluoromethyl)phenyl]-1H- thieno[2,3-c]pyrazole MS m/z (M + H⁺) 561.0 1272 1-{1-[(4-Methyl-2-pyridin-4-yl-1,3-thiazol-5- yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 455.1 1119 2,3-Diphenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 548.2 824 3-Methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-7,8-dihydropyrrolo[1,2-a]thieno[2,3- d]pyrimidin-4(6H)-one MS m/z (M + H⁺) 485.1 710 3-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-9H-xanthen-9-one MS m/z (M + H⁺) 475.1 823 5,7-Dichloro-2-methyl-3-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)quinoline MS m/z (M + H⁺) 490.0 782 1-(1-{[4-(2-Methoxyethoxy)phenyl]carbonyl}azetidin-3-yl)-4- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 431.3 698 2-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-9H-fluoren-9-one MS m/z (M + H⁺) 459.1 1123 1-[1-({4-[4-(3,5-Difluorophenyl)-1H-pyrazol-1- yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 535.2 791 5-Chloro-2,8-dimethyl-3-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)quinoline MS m/z (M + H⁺) 470.1 845 7-Methoxy-2-methyl-3-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)quinoline MS m/z (M + H⁺) 452.2 1412 1-[1-({4-[5-(4-Fluorophenyl)-1H-pyrazol-1- yl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 518.1 946 N-Methyl-N-phenyl-4-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)benzenesulfonamide MS m/z (M + H⁺) 526.0 1041 2-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenoxy]-N-[3-(trifluoromethyl)phenyl]acetamide MS m/z (M + H⁺) 574.0 1042 4-{[2,5-Dimethyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)-1H-pyrrol-1- yl]methyl}benzenesulfonamide MS m/z (M + H⁺) 544.0 947 1-(1-{[4-(Piperidin-1-ylsulfonyl)phenyl]carbonyl}azetidin-3-yl)- 4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 504.1 1053 1-(4-Chlorobenzyl)-3-methyl-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- thieno[2,3-c]pyrazole MS m/z (M + H⁺) 542.2 952 1-{1-[(9,9-Dimethyl-9H-fluoren-2-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 473.0 1407 1-[1-({4-Methyl-2-[3-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): d 8.28 (s, 1H), 8.23 (d, 1H), 7.98 (d, 1H), 7.88 (d, 1H), 7.82 (d, 1H), 7.72 (t, 1H), 4.35-4.81 (m, 6H), 3.92-4.13 (m, 3H), 3.19-3.27 (m, 4H), 2.71 (s, 3H) MS m/z (M + H⁺) 522.2 1384 1-(1-{[2-(4-Chlorophenyl)-4-methyl-1,3-thiazol-5- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 488.1 1381 1-(1-{[2-(3-Chlorophenyl)-4-methyl-1,3-thiazol-5- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 488.1 1150 1-(1-{[2-(4-Fluorophenyl)-4-methyl-1,3-thiazol-5- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 472.0 1386 1-(1-{[2-(4-Fluorophenyl)-4-methyl-1,3-thiazol-5- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 472.0 1385 1-(1-{[2-Phenyl-5-(trifluoromethyl)-1,3-oxazol-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 492.1 1378 1-{1-[(2-Methyl-5-phenylfuran-3-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 437.1 1379 1-(1-{[5-Phenyl-2-(trifluoromethyl)furan-3- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 491.1 965 1-[1-({2-[(4-Chlorophenoxy)methyl]-4-methyl-1,3-thiazol-5- yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 518.1 1392 1-(1-{[1-Phenyl-5-(trifluoromethyl)-1H-pyrazol-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 491.1 1403 1-(1-{[2-Phenyl-5-(trifluoromethyl)-1,3-oxazol-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 492.1 1396 1-{1-[(2-Methyl-5-phenylfuran-3-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 437.1 1397 1-(1-{[5-Phenyl-2-(trifluoromethyl)furan-3- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 491.1 966 1-[1-({2-[(4-Chlorophenoxy)methyl]-4-methyl-1,3-thiazol-5- yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 518.1 1477 1-(1-{[1-Phenyl-5-(trifluoromethyl)-1H-pyrazol-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 491.1 1395 1-(1-{[2-(3,5-Dichlorophenyl)-1,3-thiazol-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 507.9/508.8 923 1-(1-{[3-Bromo-5-(trifluoromethyl)phenyl]carbonyl}azetidin-3- yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 503/505 910 1-(1-{[3-Bromo-5-(trifluoromethyl)phenyl]carbonyl}azetidin-3- yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 503/505 915 1-{1-[(5-Bromo-2-fluorophenyl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 453/455 912 1-{1-[(3-Bromo-5-fluorophenyl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 453/455 925 1-{1-[(5-Bromo-2-fluorophenyl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 453/455 926 1-{1-[(3-Bromo-5-fluorophenyl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 453/455 1202 1-(1-{[2-(2-Fluorophenyl)-4-methyl-1,3-thiazol-5- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 472.2 1287 1-(1-{[2-(2-Fluorophenyl)-4-methyl-1,3-thiazol-5- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 472.2 831 1-(1-Methylethyl)-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)-2-(trifluoromethyl)-1H- benzimidazole MS m/z (M + H⁺) 507.1 740 1-(1-Methylethyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)-2-(trifluoromethyl)-1H- benzimidazole MS m/z (M + H⁺) 507.1 1432 2-(2-Oxo-2-{3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}ethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide MS m/z (M + H⁺) 476.1 517 2-Phenyl-4-[1-(phenylcarbonyl)azetidin-3-yl]-1-{[5- (trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}piperazine MS m/z (M + H⁺) 550.03 1489 3-Methyl-2-phenyl-8-({2-phenyl-4-[1-(phenylcarbonyl)azetidin- 3-yl]piperazin-1-yl}carbonyl)-4H-chromen-4-one MS m/z (M + H⁺) 584.34 1490 1-{1-[(5-Fluoro-3-methyl-1-benzofuran-2-yl)carbonyl]azetidin- 3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 422.06 526 7-Methoxy-3-methyl-2-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 433.2 610 1-[4-({4-[1-(Phenylcarbonyl)azetidin-3-yl]piperazin-1- yl}carbonyl)phenyl]-1H-benzimidazole MS m/z (M + H⁺) 466.2 523 1-Cyclohexyl-2-methyl-5-({4-[1-(phenylcarbonyl)azetidin-3- yl]piperazin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 486.3 1491 1-{1-[(5-Chloro-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 424 611 2-Phenyl-5-({4-[1-(phenylcarbonyl)azetidin-3-yl]piperazin-1- yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 466.2 524 1-[(5-Chloro-1-benzofuran-2-yl)carbonyl]-4-[1- (phenylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 432.9 502 1-(Phenylcarbonyl)-4-(1-{[4- (trifluoromethyl)cyclohexyl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 424 503 1-(1-{[4-(4-Chlorophenyl)cyclohexyl]carbonyl}azetidin-3-yl)-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 466 648 1-(1,3-Thiazol-4-ylcarbonyl)-4-{1-[(2E)-3-{4- [(trifluoromethyl)sulfanyl]phenyl}prop-2-enoyl]azetidin-3- yl}piperazine MS m/z (M + H⁺) 483.3 644 1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[4- (trifluoromethyl)cyclohexyl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 431.29 643 1-(1-{[4-(4-Chlorophenyl)cyclohexyl]carbonyl}azetidin-3-yl)-4- (1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 473.27 1481 4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-2-phenyl-1-(1,3- thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 509.28 804 2-Phenyl-4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]-1-{[5- (trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}piperazine MS m/z (M + H⁺) 557.14 905 2-Phenyl-4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]-1-{[5- (trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}piperazine ¹H NMR (CDCl₃): δ 9.02 (d, 1H); 8.31 (s, 1H); 8.22 (s, 1H); 8.12 (m, 1H); 7.77 (s, 1H); 7.69 (m, 1H); 7.50 (m, 5H); 7.35 (m, 1H); 5.91 (bm, 1H); 4.83 (m, 1H); 4.64 (m, 1H); 4.48-4.46 (m, 2H); 4.14 (m, 1H); 3.86 (m, 1H); 3.87 (m, 1H); 3.51 (m, 1H); 3.12 (t, 1H); 2.97 (m, 1H). MS m/z (M + H⁺) 557.18 1436 3-Methyl-2-phenyl-8-({2-phenyl-4-[1-(1,3-thiazol-4- ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-4H-chromen- 4-one MS m/z (M + H⁺) 591.26 854 3-Methyl-2-phenyl-8-({2-phenyl-4-[1-(1,3-thiazol-2- ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-4H-chromen- 4-one MS m/z (M + H⁺) 591.24 1307 1-(1-{[5-(4-Chlorophenyl)-1H-pyrrol-2-yl]carbonyl}azetidin-3- yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 256 1122 1-{1-[(5-Phenylthiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.99 (d, 1H), 7.88 (d, 1H); 7.71 9m, 2H); 7.52-7.32 (m, 4H); 4.75 (b, 4H); 4.0 (bm, 3H); 3.22 (bm, 4H) MS m/z (M + H⁺) 439.16 1473 1-(1-{[5-(4-Chlorophenyl)-1,3-oxazol-4-yl]carbonyl}azetidin-3- yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 458.13 838 1-Methyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 410.12 796 1,2-Dimethyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 424.21 1475 1-{1-[(3-Phenyl-1H-pyrazol-4-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 323.13 993 1-Benzyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 486 850 1-{1-[(6-Methoxy-3-methyl-1-benzofuran-2- yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 441.1 721 1-{1-[(6-Methoxy-3-methyl-1-benzofuran-2- yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 441.1 862 1-{1-[(5-Fluoro-3-methyl-1-benzofuran-2-yl)carbonyl]azetidin- 3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 429.1 751 1-{1-[(5-Fluoro-3-methyl-1-benzofuran-2-yl)carbonyl]azetidin- 3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 429.1 840 7-Methoxy-3-methyl-2-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 440.1 760 7-Methoxy-3-methyl-2-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 440.1 1442 6-Fluoro-2-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 415 846 7-Methoxy-3-methyl-2-({4-[1-(1,3-thiazol-2- ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 439.7/440.3 871 1-{1-[(7-Fluoro-3-methyl-1-benzofuran-2-yl)carbonyl]azetidin- 3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 428.8 857 7-Methoxy-3-methyl-2-({4-[1-(1,3-thiazol-4- ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 440.1 755 5-Chloro-3-methyl-2-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 444.1 1443 5-Fluoro-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 415.2 794 1-{1-[(7-Fluoro-3-methyl-1-benzofuran-2-yl)carbonyl]azetidin- 3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 428.8 688 5-Chloro-3-methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)-1H-indole ¹H NMR (CDCl₃): δ 7.88 (d, 1H); 7.78 (d, 1H); 7.5 (m, 1H); 7.27 (m, 1H); 7.12 (m, 1H); 4.16 (bm, 1H); 4.32 (bm, 2H); 3.16 (m, 3H); 2.36 (s, 3H) MS m/z (M + H⁺) 443.1 1293 1-[4-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenyl]-1H-benzimidazole MS m/z (M + H⁺) 472.83 1223 1-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenyl]-1H-benzimidazole MS m/z (M + H⁺) 473.1 1305 1-[4-({4-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]piperazin-1- yl}carbonyl)phenyl]-1H-benzimidazole MS m/z (M + H⁺) 473.1 1298 1-[4-({4-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1- yl}carbonyl)phenyl]-1H-benzimidazole MS m/z (M + H⁺) 473.1 732 1-Cyclohexyl-2-methyl-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 493.2 793 1-Cyclohexyl-2-methyl-5-({4-[1-(1,3-thiazol-2- ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 493.2 814 1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}-4-(1-{[4-(trifluoromethyl)-1,3-thiazol-2- yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 563.1 800 2-Cyclohexyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 479.1 735 2-Cyclohexyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 479.1 827 2-Cyclohexyl-5-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3- yl]piperazin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 479.1 853 2-Cyclohexyl-5-({4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3- yl]piperazin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 479.1 1299 2-Phenyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 473.1 1194 2-Phenyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 473.1 1271 2-Phenyl-5-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3- yl]piperazin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 473.1 1444 1-{1-[(5-Chloro-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 431 818 1-{1-[(5-Chloro-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 431 785 1-[(5-Chloro-1-benzofuran-2-yl)carbonyl]-4-[1-(1,3-thiazol-2- ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 430.86 809 1-[(5-Chloro-1-benzofuran-2-yl)carbonyl]-4-[1-(1,3-thiazol-4- ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 430.93 1000 2-(2-Phenylethyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 501.1 1001 2-Benzyl-6-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3- yl]piperazin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 486.9 855 5-Chloro-2-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,3-benzothiazole MS m/z (M + H⁺) 447.6 1002 2-(2-Phenylethyl)-6-({4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3- yl]piperazin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 501.1 728 5-Chloro-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,3-benzothiazole MS m/z (M + H⁺) 448 764 5-Chloro-2-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3- yl]piperazin-1-yl}carbonyl)-1,3-benzothiazole MS m/z (M + H⁺) 448 1003 2-Benzyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 487 1004 2-Benzyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 487 821 5-Chloro-2-({4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3- yl]piperazin-1-yl}carbonyl)-1,3-benzothiazole MS m/z (M + H⁺) 448.1 779 4-Chloro-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-2-(trifluoromethyl)quinoline MS m/z (M + H⁺) 5.1 848 4-Chloro-6-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-2-(trifluoromethyl)quinoline MS m/z (M + H⁺) 509.72 859 4-Chloro-6-({4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3- yl]piperazin-1-yl}carbonyl)-2-(trifluoromethyl)quinoline MS m/z (M + H⁺) 510 842 4-Chloro-6-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3- yl]piperazin-1-yl}carbonyl)-2-(trifluoromethyl)quinoline MS m/z (M + H⁺) 510 756 2-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-6-(trifluoromethyl)-1H-indole MS m/z (M + H⁺) 463.81 828 2-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-6-(trifluoromethyl)-1H-indole MS m/z (M + H⁺) 463.81 1445 2-({3-[4-(Isothiazol-5-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-6-(trifluoromethyl)-1H-indole MS m/z (M + H⁺) 463.81 747 2-({4-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1- yl}carbonyl)-5-(trifluoromethyl)-1H-indole MS m/z (M + H⁺) 464.1 772 2-({4-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]piperazin-1- yl}carbonyl)-5-(trifluoromethyl)-1H-indole MS m/z (M + H⁺) 464.1 726 1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}-4-[1-(1,3-thiazol-5-ylcarbonyl)azetidin-3- yl]piperazine MS m/z (M + H⁺) 494.97 731 1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}-4-[1-(1H-pyrrol-2-ylcarbonyl)azetidin-3- yl]piperazine MS m/z (M + H⁺) 477.02 748 1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}-4-[1-(1H-pyrrol-3-ylcarbonyl)azetidin-3- yl]piperazine MS m/z (M + H⁺) 477.02 844 2-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-6-(trifluoromethyl)furo[2,3-b]pyridine MS m/z (M + H⁺) 466.1 808 2-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-6-(trifluoromethyl)furo[2,3-b]pyridine MS m/z (M + H⁺) 465.98 1446 2-({3-[4-(1H-Pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-6-(trifluoromethyl)furo[2,3-b]pyridine MS m/z (M + H⁺) 448.2 860 2-({4-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]piperazin-1- yl}carbonyl)-6-(trifluoromethyl)furo[2,3-b]pyridine MS m/z (M + H⁺) 466 678 1-[1-(Phenoxathiin-2-ylcarbonyl)azetidin-3-yl]-4-(1H-pyrrol-2- ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.38 (m, 2H); 7.19-6.84 (m, 5H); 6.88 (m, 1H); 6.56 (m, 1H); 6.13 (m, 1H); 4.67-4.21 (m, 3H); 4.12-3.90 (bd, 4H); 3.25 (bm, 3H) MS m/z (M + H⁺) 461.2 799 2-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine MS m/z (M + H⁺) 465.2 865 2-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine MS m/z (M + H⁺) 465.1 1447 2-({3-[4-(1H-Pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine MS m/z (M + H⁺) 447.1 1448 5-Bromo-2-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)furo[2,3-b]pyridine MS m/z (M + H⁺) 477.1 864 5-Bromo-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)furo[2,3-b]pyridine MS m/z (M + H⁺) 477.1 1449 5-Bromo-2-({4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3- yl]piperazin-1-yl}carbonyl)furo[2,3-b]pyridine MS m/z (M + H⁺) 477.1 696 5-Chloro-1,3-dimethyl-2-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 458.2 758 5-Chloro-1,3-dimethyl-2-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 458.1 762 5-Chloro-1,3-dimethyl-2-({4-[1-(1,3-thiazol-2- ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 485.1 839 5-Chloro-1,3-dimethyl-2-({4-[1-(1H-pyrrol-2- ylcarbonyl)azetidin-3-yl]piperazin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 440.2 774 3-Bromo-2-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3- b]pyridine MS m/z (M + H⁺) 543.1 733 5-Chloro-1,3-dimethyl-2-({3-[4-(1H-pyrrol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 440.2 675 3-Bromo-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3- b]pyridine MS m/z (M + H⁺) 543.1 739 3-Bromo-2-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3- b]pyridine MS m/z (M + H⁺) 525.2 746 3-Bromo-2-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3- yl]piperazin-1-yl}carbonyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3- b]pyridine MS m/z (M + H⁺) 543 863 2-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine MS m/z (M + H⁺) 465.1 830 2-({4-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]piperazin-1- yl}carbonyl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine MS m/z (M + H⁺) 465.1 1450 2-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine MS m/z (M + H⁺) 465.1 719 5-Fluoro-3-methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 428.3 852 6-Bromo-7-methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)imidazo[1,2-a]pyridine MS m/z (M + H⁺) 495.1 1451 6-Bromo-7-methyl-2-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)imidazo[1,2-a]pyridine MS m/z (M + H⁺) 472.8 1452 8-Bromo-6-chloro-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)imidazo[1,2-a]pyridine MS m/z (M + H⁺) 472.8 1453 2-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine MS m/z (M + H⁺) 465.1 682 5-Bromo-3-methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 488.1 868 6-Bromo-3-methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)imidazo[1,2-a]pyridine MS m/z (M + H⁺) 490.1 873 6-Bromo-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)imidazo[1,2-a]pyridine MS m/z (M + H⁺) 475 825 6-Bromo-3-methyl-2-({3-[4-(1H-pyrrol-2-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)imidazo[1,2-a]pyridine MS m/z (M + H⁺) 471.1 792 6-Bromo-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 476.1 953 (2R,6S)-2,6-Dimethyl-4-(1,3-thiazol-2-ylcarbonyl)-1-(1-{[6- (trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3- yl)piperazine MS m/z (M + H⁺) 509.0

Example 6

A. Azetidin-3-one, 6a

The title compound 6a was prepared using the method described in Example 1, substituting compound 4a for compound 1c in Procedure B. The crude compound 6a was used in the next reaction without further purification. MS m/z (M+H⁺+CF₃CO₂H) 186.1.

B. 1-(4-Bromo-benzoyl)-azetidin-3-one, 6b

The title compound 6b was prepared using the method described in Example 1, substituting compound 6a for compound 1g and substituting compound 2d for compound 1h in Procedure E. The crude compound 6b was used in the next reaction without further purification. MS m/z (M+H⁺) 419.2.

C. 4-[1-(4-Bromo-benzoyl)-azetidin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester, 6c

The title compound 6c was prepared using the method described in Example 4, substituting compound 6b for compound 4a and substituting compound 1a for compound 2a in Procedure A. The crude product 6c was purified by flash column chromatography. MS m/z (M+H⁺) 424.0/426.1.

D. (4-Bromo-phenyl)-(3-piperazin-1-yl-azetidin-1-A-methanone, 6d

The title compound 6d was prepared using the method described in Example 1, substituting compound 6c for compound 1c in Procedure B. The crude product 6d was used in the next reaction without further purification. MS m/z (M+H⁺) 324.08/326.08.

E. 1-{1-[(4-Bromophenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 173

The title compound Cpd 173 was prepared using the method described in Example 1, substituting compound 6d for compound 1g and substituting compound 5c for compound 1h in Procedure E. The crude product Cpd 173 was used in the next reaction without further purification. MS m/z (M+H⁺) 435.0/437.0.

F. 1-{1-[(4′-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 174

To a suspension of compound 173 (0.05 g, 0.115 mmol), compound 6e (0.0193 g, 0.14 mmol), and Cs₂CO₃ (0.094 g, 0.288 mmol) in dioxane (3 mL) and EtOH (1 mL) was added Pd(dppf)Cl₂ (0.0084 g, 0.0115 mmol). The reaction mixture was stirred at 80° C. for 3 h. After cooling, the solid was removed by filtration and washed with CH₃OH. The filtrate was concentrated. The crude compound 174 was purified by reverse phase chromatography. ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.87 (d, 1H), 7.65-7.79 (m, 6H), 7.21 (t, 2H), 4.67 (m, 3H), 4.52 (m, 1H), 4.43 (m, 1H), 4.31 (m, 1H), 3.98 (m, 2H), 3.89 (m, 1H), 3.11 (m, 4H); MS m/z (M+H⁺) 451.2 (calculated for C₂₄H₂₃FN₄O₂S, 450.54).

Following the procedure described above for Example 6 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 175 1-{1-[(3′,4′-Dichlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.98 (d, 1H), 7.88 (d, 1H), 7.85 (d, 1H), 7.77 (m, 4H), 7.62 (m, 2H), 4.54-4.81 (m, 4H) 4.46 (m, 1H), 4.38 (m, 1H), 4.04 (m, 3H), 3.25 (m, 4H); LC/MS m/z (M + H⁺) 501.0/503.1 (calculated for C₂₄H₂₂Cl₂N₄O₂, 501.44) 176 1-{1-[(3′-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.87 (d, 1H), 7.74 (m, 4H), 7.45 (m, 2H), 7.35 (t, 1H), 7.22 (d, 1H), 4.68 (m, 3H), 4.53 (m, 1H), 4.44 (m, 1H), 4.32 (m, 1H), 3.87-4.05 (m, 3H), 3.15 (m, 4H); LC/MS m/z (M + H⁺) 447.1 (calculated for C₂₅H₂₆N₄O₂S, 446.58) 177 1-{1-[(5′-Fluoro-2′-methylbiphenyl-4-yl)carbonyl]azetidin-3- yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.87 (d, 1H), 7.76 (d, 2H), 7.46 (d, 2H), 7.30 (dd, 1H), 7.02 (td, 1H), 6.94 (dd, 1H), 4.68 (m, 3H), 4.55 (m, 1H), 4.44 (m, 1H), 4.33 (m, 1H), 4.01 (m, 2H), 3.92 (m, 1H), 3.14 (m, 4H); LC/MS m/z (M + H⁺) 465.1 (calculated for C₂₅H₂₅FN₄O₂S, 464.57) 178 1-{1-[(3′-Chloro-4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3- yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.87 (d, 1H), 7.80 (dd, 1H), 7.76 (m, 4H), 7.64 (m, 1H), 7.36 (t, 1H), 4.68 (m, 3H), 4.52 (m, 1H), 4.45 (m, 1H), 4.32 (m, 1H), 3.89-4.06 (m, 3H), 3.16 (m, 4H); LC/MS m/z (M + H⁺) 485.1 (calculated for C₂₄H₂₂ClFN₄O₂S, 484.98) 179 1-{1-[(2′,4′-Difluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.87(d, 1H), 7.77 (d, 2H), 7.65 (d, 2H), 7.55 (m, 1H), 7.10 (m, 2H), 4.65 (m, 3H), 4.50 (m, 1H), 4.42 (m, 1H), 4.30 (m, 1H), 3.97 (m, 2H), 3.86 (m, 1H), 3.07 (m, 4H); LC/MS m/z (M + H⁺) 469.0 (calculated for C₂₄H₂₂F₂N₄O₂S, 468.53) 180 1-{1-[(3′-Methoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.87 (d, 1H), 7.75 (m, 4H), 7.39 (t, 1H), 7.22 (d, 1H), 7.18 (t, 1H), 6.97 (dd, 1H), 4.67 (m, 3H), 4.51 (m, 1H), 4.43 (m, 1H), 4.32 (m, 1H), 3.96 (m, 3H), 3.86 (s, 3H), 3.15 (m, 4H); LC/MS m/z (M + H⁺) 463.2 (calculated for C₂₅H₂₆N₄O₃S, 462.57) 181 1-(1-{[4-(1,3-Benzodioxol-5-yl)phenyl]carbonyl}azetidin-3- yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.98 (d, 1H), 7.87 (d, 1H), 7.70 (m, 4H), 7.16 (m, 2H), 6.92 (d, 1H), 6.01 (s, 2H), 4.69 (m, 3H), 4.54 (m, 1H), 4.44 (m, 1H), 4.33(m, 1H), 3.97 (m, 3H), 3.17 (m, 4H); LC/MS m/z (M + H⁺) 477.1 (calculated for C₂₅H₂₄N₄O₄S, 476.56) 182 1-{1-[(4-Naphthalen-2-ylphenyl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.79-8.01 (m, 11H), 7.50- 7.56 (m, 2H), 4.60 (m, 1H), 4.49 (m, 1H), 4.37 (m, 1H), 4.27 (m, 1H), 4.08 (m, 4H), 3.95 (m, 1H), 3.14 (m, 4H); LC/MS m/z (M + H⁺) 483.1 (calculated for C₂₈H₂₆N₄O₂S, 482.61) 183 1-{1-[(3′-Nitrobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 8.53 (t, 1H), 8.29 (m, 1H), 8.10 (m, 1H), 7.97 (d, 1H), 7.82-7.90 (m, 5H), 7.75 (t, 1H), 4.69 (m, 3H), 4.55 (m, 1H), 4.46 (m, 1H), 4.34 (m, 1H), 3.88- 4.07 (m, 3H), 3.15 (m, 4H); LC/MS m/z (M + H⁺) 478.2 (calculated for C₂₄H₂₃N₅O₄S, 477.55) 184 5-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)phenyl]quinoline ¹H NMR (300 MHz, CD₃OD): δ 9.14 (d, 1H), 8.80 (d, 1H), 8.24 (d, 1H), 8.13 (dd, 1H), 7.97 (d, 1H), 7.89 (m, 5H), 7.68 (m, 2H), 4.70 (m, 3H), 4.60 (m, 1H), 4.47 (m, 1H), 4.36 (m, 1H), 4.00 (m, 2H), 3.91 (m, 1H), 3.12 (m, 4H); LC/MS m/z (M + H⁺) 484.2 (calculated for C₂₇H₂₅N₅O₂S, 483.6) 185 1-{1-[(2′,4′-Dimethoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}- 4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 486.1 186 1-(Phenylcarbonyl)-4-(1-{[3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.94 (m, 2H), 7.80 (m, 4H), 7.70 (m, 2H), 7.45-7.53 (m, 5H), 4.66 (m, 1H), 4.52 (m, 1H), 4.44 (m, 1H), 4.31 (m, 1H), 3.95 (m, 1H), 3.84 (m, 4H), 3.10 (m, 4H); LC/MS m/z (M + H⁺) 494.1 (calculated for C₂₈H₂₆F₃N₃O₂, 493.53) 187 1-{1-[(2′-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 444.1 188 1-(1-{[3′-(1-Methylethoxy)biphenyl-4-yl]carbonyl}azetidin-3- yl)-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.73 (m, 4H), 7.48 (m, 5H), 7.36 (t, 1H), 7.19 (d, 1H), 7.14 (t, 1H), 6.94 (dd, 1H), 4.19- 4.82 (m, 5H), 3.83 (m, 5H), 2.98 (m, 4H), 1.34 (d, 6H); LC/MS m/z (M + H⁺) 484.2 (calculated for C₃₀H₃₃N₃O₃, 483.62) 189 1-(Phenylcarbonyl)-4-(1-{4′-(trifluoromethoxy)biphenyl-4- yl]carbonyl}azetidin-3-yl)piperazine LC/MS m/z (M + H⁺) 510.1 190 1-(1-{[4-(2-Fluoropyridin-4-yl)phenyl]carbonyl}azetidin-3- yl)-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 445.2 191 1-{1-[(3′-Fluoro-4′-methoxybiphenyl-4-yl)carbonyl]azetidin-3- yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 474.1 192 Methyl 4′-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)biphenyl-4-carboxylate LC/MS m/z (M + H⁺) 484.2 193 1-(Phenylcarbonyl)-4-{1-[(3′,4′,5′-trifluorobiphenyl-4- yl)carbonyl]azetidin-3-yl}piperazine LC/MS m/z (M + H⁺) 480.1 194 N,N-Diethyl-4′-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)biphenyl-3-carboxamide LC/MS m/z (M + H⁺) 525.3 195 1-{1-[(3′-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.76 (m, 4H), 7.38-7.54 (m, 8H), 7.13 (m, 1H), 4.66 (m, 1H), 4.53 (m, 1H), 4.43 (m, 1H), 4.31 (m, 1H), 3.95 (m, 1H), 3.83 (m, 4H), 3.11 (m, 4H); LC/MS m/z (M + H⁺) 444.1 (calculated for C₂₇H₂₆FN₃O₂, 443.53) 196 1-(Phenylcarbonyl)-4-(1-{2′-(trifluoromethoxy)biphenyl-4- yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.77(d, 2H), 7.60 (d, 2H), 7.39-7.55 (m, 9H), 4.68 (m, 1H), 4.57 (m, 1H), 4.45 (m, 1H), 4.33 (m, 1H), 3.97 (m, 1H), 3.83 (m, 4H), 3.13 (m, 4H); LC/MS m/z (M + H⁺) 510.1 (calculated for C₂₈H₂₆F₃N₃O₃, 509.53) 197 1-{1-[(4′-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 440.2 198 1-(1-{[2′-(1-Methylethoxy)biphenyl-4-yl]carbonyl}azetidin-3- yl)-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 484.2 199 Methyl 4′-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)biphenyl-2-carboxylate LC/MS m/z (M + H⁺) 484.2 200 1-{1-[(4′-Fluoro-2′-methoxybiphenyl-4-yl)carbonyl]azetidin-3- yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 474.3 201 1-{1-[(2′,3′-Dimethoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}- 4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 486.3 202 1-{1-[(2′,5′-Difluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 462.1 203 1-{1-[(2′-Fluoro-6′-methoxybiphenyl-4-yl)carbonyl]azetidin-3- yl}-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 474.3 204 1-{1-[(2′,3′-Difluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 462.1 205 N,N-Dimethyl-N′-[4′-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)biphenyl-3-yl]sulfamide ¹H NMR (300 MHz, CD₃OD): δ 7.73 (dd, 4H), 7.33-7.54 (m, 8H), 7.23 (dt, 1H), 4.18-4.72 (m, 4H), 3.83 (m, 5H), 3.01 (m, 4H), 2.80 (s, 6H); LC/MS m/z (M + H⁺) 548.3 (calculated for C₂₉H₃₃N₅O₄S, 547.68) 206 4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)biphenyl-3-carboxylic acid LC/MS m/z (M + H⁺) 477.1 207 [4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)biphenyl-3-yl]acetonitrile ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.87 (d, 1H), 7.78 (m, 4H), 7.65 (m, 2H), 7.51 (t, 1H), 7.42 (d, 1H), 4.25- 4.76 (m, 6H), 4.00 (s, 2H), 3.86-4.03 (m, 3H), 3.13 (m, 4H); LC/MS m/z (M + H⁺) 472.2 (calculated for C₂₆H₂₅N₅O₂S, 471.59) 208 1-(1-{[3′-(Methylsulfonyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 8.22 (m, 1H), 7.95-8.07 (m, 3H), 7.71-7.90 (m, 6H), 4.31-4.81 (m, 6H), 4.03 (m, 3H), 3.21- 3.36 (m, 4H), 3.19 (s, 3H); LC/MS m/z (M + H⁺) 511.2 (calculated for C₂₅H₂₆N₄O₄S₂, 510.64) 209 1-[4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)biphenyl-4-yl]ethanone ¹H NMR (300 MHz, CD₃OD): δ 8.11 (d, 2H), 7.97 (d, 1H), 7.76-7.91 (m, 7H), 4.70 (m, 3H), 4.55 (m, 1H), 4.45 (m, 1H), 4.34 (m, 1H), 3.98 (m, 3H), 3.16 (m, 4H), 2.65 (s, 3H); LC/MS m/z (M + H⁺) 475.2 (calculated for C₂₆H₂₆N₄O₃S, 474.59) 210 4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)biphenyl-3-carbaldehyde ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.87 (d, 1H), 7.76 (m, 4H), 7.72 (m, 1H), 7.65 (m, 1H), 7.49 (m, 2H), 4.69 (m, 3H), 4.53 (m, 1H), 4.44 (m, 1H), 4.32 (m, 1H), 3.96 (m, 3H), 3.15 (m, 4H); LC/MS m/z (M + H⁺) 461.2 (calculated for C₂₅H₂₄N₄O₃S, 460.56) 211 4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)biphenyl-4-ol ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.86(d, 1H), 7.69 (m, 4H), 7.52 (d, 2H), 6.88 (d, 2H), 4.66 (m, 3H), 4.51 (m, 1H), 4.42 (m, 1H), 4.29 (m, 1H), 3.98 (m, 2H), 3.86 (m, 1H), 3.09 (m, 4H); LC/MS m/z (M + H⁺) 449.2 (calculated for C₂₄H₂₄N₄O₃S, 448.55) 212 1-(1-{[4′-Chloro-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 8.03 (d, 1H), 7.97 (d, 1H), 7.92 (dd, 1H), 7.86 (d, 1H), 7.80 (m, 4H), 7.73 (d, 1H), 4.62 (m, 3H), 4.45 (m, 2H), 4.28 (m, 1H), 3.96 (m, 2H), 3.82 (m, 1H), 3.03 (m, 4H); LC/MS m/z (M + H⁺) 535.0 (calculated for C₂₅H₂₂ClF₃N₄O₂S, 534.99) 213 N,N-Dimethyl-4′-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)biphenyl-4-sulfonamide ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.78-7.95 (m, 9H), 4.70 (m, 3H), 4.55 (m, 1H), 4.45 (m, 1H), 4.34 (m, 1H), 3.97 (m, 3H), 3.17 (m, 4H), 2.72 (s, 6H); LC/MS m/z (M + H⁺) 540.2 (calculated for C₂₆H₂₉N₅O₄S₂, 539.68) 214 1-{1-[(4′,5′-Difluoro-2′-methoxybiphenyl-4- yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.88 (d, 1H), 7.71 (d, 2H), 7.69 (d, 2H), 7.26 (dd, 1H), 7.08 (dd, 1H), 4.70 (m, 3H), 4.56 (m, 1H), 4.46 (m, 1H), 4.35 (m, 1H), 3.99 (m, 3H), 3.20 (m, 4H); LC/MS m/z (M + H⁺) 499.2 (calculated for C₂₅H₂₄F₂N₄O₃S, 498.56) 215 1-{1-[(4′-Nitrobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 8.36 (d, 2H), 7.78-7.99 (m, 8H), 4.67 (m, 3H), 4.52 (m, 1H), 4.44 (m, 1H), 4.31 (m, 1H), 3.98 (m, 2H), 3.99 (m, 1H), 3.12 (m, 4H); LC/MS m/z (M + H⁺) 478.2 (calculated for C₂₄H₂₃N₅O₄S, 477.55) 216 4-Methoxy-4′-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)biphenyl-3-carbaldehyde ¹H NMR (300 MHz, CD₃CN): δ 10.38 (s, 1H), 7.96 (d, 1H), 7.84-7.91 (m, 2H), 7.59-7.69 (m, 5H), 7.19 (d, 1H), 4.33-4.64 (m, 4H), 4.23 (m, 2H), 3.91 (s, 3H), 3.89 (m, 1H), 3.74 (m, 2H), 3.02 (m, 4H); LC/MS m/z (M + H⁺) 491.2 (calculated for C₂₆H₂₆N₄O₄S, 490.59) 217 4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)biphenyl-3-carboxamide LC/MS m/z (M + H⁺) 476.1 218 4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)biphenyl-3-ol ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.87 (d, 1H), 7.72 (m, 4H), 7.28 (t, 1H), 7.11 (d, 1H), 7.06 (t, 1H), 6.82 (dd, 1H), 4.64 (m, 3H), 4.49 (m, 1H), 4.40 (m, 1H), 4.28 (m, 1H), 3.96 (m, 2H), 3.81 (m, 1H), 3.03 (m, 4H); LC/MS m/z (M + H⁺) 449.2 (calculated for C₂₄H₂₄N₄O₃S, 448.55) 219 N-[4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)biphenyl-3-yl]methanesulfonamide ¹H NMR (300 MHz, CD₃OD): δ 7.98 (d, 1H), 7.88 (d, 1H), 7.76 (m, 4H), 7.55 (t, 1H), 7.45 (m, 2H), 7.28 (m, 1H), 4.73 (m, 3H), 4.60 (m, 1H), 4.47 (m, 1H), 4.38 (m, 1H), 4.03 (m, 3H), 3.26 (m, 4H), 3.00 (s, 1H); LC/MS m/z (M + H⁺) 526.2 (calculated for C₂₅H₂₇N₅O₄S₂, 525.65) 220 tert-Butyl [4′-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)biphenyl-3-yl]carbamate ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.87 (d, 1H), 7.80 (m, 1H), 7.75 (m, 4H), 7.37 (m, 2H), 7.30 (m, 1H), 4.69 (m, 3H), 4.52 (m, 1H), 4.44 (m, 1H), 4.31 (m, 1H), 3.85-4.07 (m, 3H), 3.13 (m, 4H), 1.53 (s, 9H); LC/MS m/z (M + H⁺) 548.3 (calculated for C₂₉H₃₃N₅O₄S, 547.68) 221 1-(1-{[3′-(2-Methylpropoxy)biphenyl-4-yl]carbonyl}azetidin- 3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.87 (d, 1H), 7.75 (m, 4H), 7.37 (t, 1H), 7.21 (d, 1H), 7.17 (t, 1H), 6.96 (dd, 1H), 4.67 (m, 3H), 4.52 (m, 1H), 4.43 (m, 1H), 4.30 (m, 1H), 3.76-4.04 (m, 5H), 3.10 (m, 4H), 2.08 (m, 1H), 1.06 (d, 6H); LC/MS m/z (M + H⁺) 505.2 (calculated for C₂₈H₃₂N₄O₃S, 504.66) 222 N-(2-Cyanoethyl)-4′-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)biphenyl-3- carboxamide LC/MS m/z (M + H⁺) 529.2 223 3-[4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)biphenyl-3-yl]prop-2-enenitrile ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 8.14 (s, 1H), 7.89 (m, 1H), 7.86 (d, 1H), 7.79 (m, 4H), 7.76 (m, 1H), 7.50- 7.69 (m, 2H), 6.36 (d, 1H), 4.62 (m, 3H), 4.48 (m, 1H), 4.40 (m, 1H), 4.27 (m, 1H), 4.95 (m, 2H), 3.77 (m, 1H), 3.00 (m, 4H); LC/MS m/z (M + H⁺) 484.2 (calculated for C₂₇H₂₅N₅O₂S, 483.6) 224 Methyl 3-[4′-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)biphenyl-4-yl]prop-2-enoate ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.87 (d, 1H), 7.79 (m, 4H), 7.74 (m, 5H), 6.60 (d, 1H), 4.66 (m, 3H), 4.53 (m, 1H), 4.43 (m, 1H), 4.31 (m, 1H), 3.98 (m, 2H), 3.88 (m, 1H), 3.80 (s, 3H), 3.11 (m, 4H); LC/MS m/z (M + H⁺) 517.2 (calculated for C₂₈H₂₈N₄O₄S, 516.62) 225 1-{1-[(4′-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-4-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.22 (s, 1H), 7.74 (m, 4H), 7.69 (dd, 2H), 7.21 (t, 2H), 4.67 (m, 1H), 4.56 (m, 1H), 4.45 (m, 1H), 4.34 (m, 1H), 3.94-4.22 (m, 5H), 3.18 (m, 4H); LC/MS m/z (M + H⁺) 451.2 (calculated for C₂₄H₂₃FN₄O₂S, 450.54) 226 1-{1-[(2′,4′-Difluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-4-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.22 (s, 1H), 7.77 (d, 2H), 7.65 (d, 2H), 7.55 (m, 1H), 7.12 (m, 1H), 7.08 (d, 1H), 4.69 (m, 1H), 4.57 (m, 1H), 4.45 (m, 1H), 4.36 (m, 1H), 3.94-4.22 (m, 5H), 3.20 (m, 4H); LC/MS m/z (M + H⁺) 469.1 (calculated for C₂₄H₂₂F₂N₄O₂S, 468.53) 227 1-{1-[(3′-Chloro-4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3- yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.22 (s, 1H), 7.79 (dd, 1H), 7.76 (m, 4H), 7.63 (m, 1H), 7.35 (t, 1H), 4.67 (m, 1H), 4.56 (m, 1H), 4.46 (m, 1H), 4.35 (m, 1H), 3.95-4.23 (m, 5H), 3.21 (m, 4H); LC/MS m/z (M + H⁺) 485.1 (calculated for C₂₄H₂₂ClFN₄O₂S, 484.98) 228 1-{1-[(3′,4′-Dichlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-4-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 8.96 (s, 1H), 8.12 (s, 1H), 7.75 (d, 1H), 7.67 (m, 4H), 7.52 (m, 2H), 4.57 (m, 1H), 4.50 (m, 1H), 4.37 (m, 1H), 4.27 (m, 1H), 3.88-4.15 (m, 5H), 3.13 (m, 4H); LC/MS m/z (M + H⁺) 501.1 (calculated for C₂₄H₂₂Cl₂N₄O₂S, 501.44) 229 1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[3′- (trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.23 (s, 1H), 7.94 (m, 2H), 7.80 (m, 4H), 7.70 (m, 2H), 4.67 (m, 2H), 4.45 (m, 2H), 4.01-4.29 (m, 5H), 3.30 (m, 4H); LC/MS m/z (M + H⁺) 501.1 (calculated for C₂₅H₂₃F₃N₄O₂S, 500.55) 230 4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)biphenyl-3-amine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.87 (d, 1H), 7.79 (m, 4H), 7.75 (d, 1H), 7.63 (m, 2H), 7.38 (d, 1H), 4.52- 4.80 (m, 4H), 4.45 (m, 1H), 4.38 (m, 1H), 3.89-4.10 (m, 3H), 3.17 (m, 4H); LC/MS m/z (M + H⁺) 448.0 (calculated for C₂₄H₂₅N₅O₂S, 447.56) 231 1-(1-{[3′-(Methylsulfonyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)-4-(phenylcarbonyl)piperazine LC/MS m/z (M + H⁺) 504.0 232 1-(1-{[4′-Chloro-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz, DMSO-d₆): δ 8.21 (s, 1H), 8.10 (d, 1H), 7.97 (d, 1H), 7.89 (d, 2H), 7.79 (m, 3H), 7.48 (m, 4H), 4.62 (m, 2H), 4.40 (m, 1H), 4.30 (m, 1H), 4.10 (m, 1H), 3.86 (m, 4H), 3.55 (m, 2H), 3.06 (m, 2H); LC/MS m/z (M + H⁺) 528.0 (calculated for C₂₈H₂₅ClF₃N₃O₂, 527.98) 233 N-[4′-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)biphenyl-3-yl]acetamide LC/MS m/z (M + H⁺) 483.3 234 N-[4′-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)biphenyl-3-yl]acetamide ¹H NMR (300 MHz, DMSO-d₆): δ 8.10 (d, 1H), 8.06 (d, 1H), 8.00 (m, 1H), 7.75 (d, 2H), 7.70 (d, 2H), 7.57 (dt, 1H), 7.34- 7.46 (m, 2H), 4.61 (m, 2H), 4.37 (m, 1H), 4.29 (m, 1H), 4.05 (m, 1H), 3.35-3.82 (m, 6H), 3.09 (m, 2H), 2.07 (s, 3H); LC/MS m/z (M + H⁺) 490.2 (calculated for C₂₆H₂₇N₅O₃S, 489.6) 235 N-[4′-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)biphenyl-3-yl]acetamide LC/MS m/z (MH+) 490.2 236 1-(1-{[3′-(Methylsulfonyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 511.2 237 1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[3′- (trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine ¹H NMR (300 MHz, DMSO-d₆): δ 8.01-8.14 (m, 4H), 7.88 (d, 2H), 7.67-7.83 (m, 4H), 4.60 (m, 2H), 4.39 (m, 1H), 4.28 (m, 1H), 4.06 (m, 2H), 3.22-3.85 (m, 5H), 3.10 (m, 2H); LC/MS m/z (M + H⁺) 501.1 (calculated for C₂₅H₂₃F₃N₄O₂S, 500.55) 238 1-(1-{[3-Methyl-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.85-7.94 (m, 2H), 7.40-7.73 (m, 10H), 4.42 (m, 1H), 4.26 (m, 2H), 4.16 (m, 1H), 3.61-3.96 (m, 5H), 2.99 (m, 4H), 2.47 (s, 3H); LC/MS m/z (M + H⁺) 508.2 (calculated for C₂₉H₂₈F₃N₃O₂, 507.56) 239 1-(1-{[3-Methyl-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.85-8.01 (m, 4H), 7.54-7.72 (m, 4H), 7.45 (d, 1H), 4.69 (m, 2H), 4.44 (m, 1H), 4.29 (m, 2H), 4.20 (m, 1H), 3.99 (m, 2H), 3.90 (m, 1H), 3.10 (m, 4H), 2.49 (s, 3H); LC/MS m/z (M + H⁺) 515.1 (calculated for C₂₆H₂₅F₃N₄O₂S, 514.57) 240 1-(1-{[3-Methyl-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.04 (s, 1H), 8.21 (s, 1H), 7.89 (m, 2H), 7.51-7.72 (m, 4H), 7.45 (d, 1H), 3.87-4.54 (m, 9H) 3.14 (m, 4H), 2.48 (s, 3H); LC/MS m/z (M + H⁺) 515.1 (calculated for C₂₆H₂₅F₃N₄O₂S, 514.57) 241 1-(1-{[2-Methyl-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.98 (d, 1H), 7.88 (d, 1H), 7.54-7.77 (m, 6H), 7.36 (d, 1H), 4.64-4.80 (m, 3H), 4.59 (m, H), 4.48 (m, 1H), 4.38 (m, 1H), 3.92-4.12 (m, 3H), 3.27 (m, 4H), 2.30 (s, 3H); LC/MS m/z (M + H⁺) 515.1 (calculated for C₂₆H₂₅F₃N₄O₂S, 514.57) 242 1-(1-{[2-Methyl-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.07 (s, 1H), 8.22 (s, 1H), 7.49-7.78 (m, 6H), 7.34 (d, 1H), 4.66 (m, 1H), 4.39-4.58 (m, 2H), 4.33 (m, 1H), 3.87-4.20 (m, 5H), 3.14 (m, 4H), 2.31 (s, 3H); LC/MS m/z (M + H⁺) 515.1 (calculated for C₂₆H₂₅F₃N₄O₂S, 514.57) 243 1-(1-{[2-Methyl-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.44-7.75 (m, 11H), 7.34 (d, 1H), 4.64 (m, 1H), 4.34-4.55 (m, 2H), 4.29 (m, 1H), 3.66- 3.97(m, 5H), 3.03 (m, 4H), 2.30 (s, 3H); LC/MS m/z (M + H⁺) 508.2 (calculated for C₂₉H₂₈F₃N₃O₂, 507.56) 244 1-(1-{[3-Fluoro-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.91-8.05 (m, 3H), 7.87 (d, 1H), 7.56-7.80 (m, 5H), 4.60-4.77 (m, 2H), 4.38-4.51 (m, 2H), 4.24-4.38 (m, 2H), 3.84-4.09 (m, 3H), 3.10 (m, 4H); LC/MS m/z (M + H⁺) 519.2 (calculated for C₂₅H₂₂F₄N₄O₂S, 518.54) 245 1-(1-{[3-Fluoro-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.20 (s, 1H), 7.95 (m, 2H), 7.55-7.80 (m, 5H), 4.38-4.51 (m, 2H), 4.25-4.38 (m, 2H), 3.86-4.19 (m, 5H), 3.08 (m, 4H); LC/MS m/z (M + H⁺) 519.2 (calculated for C₂₅H₂₂F₄N₄O₂S, 518.54) 246 1-(1-{[3-Fluoro-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.90-8.01 (m, 2H), 7.56-7.80 (m, 5H), 7.42-7.56 (m, 5H), 4.35-4.50 (m, 2H), 4.20-4.35 (m, 2H), 3.66-3.98 (m, 5H), 3.00 (m, 4H); LC/MS m/z (M + H⁺) 512.1 (calculated for C₂₈H₂₅F₄N₃O₂, 511.52) 247 1-(1-{[2-Methoxy-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.79 (d, 1H), 7.88 (d, 1H), 7.71-7.82 (m, 2H), 7.56-7.69 (m, 2H), 7.45 (d, 1H), 7.39 (d, 1H), 7.34 (dd, 1H), 4.61-4.78 (m, 3H), 4.57 (m, 1H), 4.46 (m, 1H), 4.34 (m, 1H), 3.87-4.06 (m, 3H), 3.89 (s, 3H), 3.17 (m, 4 H); LC/MS m/z (M + H⁺) 531.2 (calculated for C₂₆H₂₅F₃N₄O₃S, 530.57) 248 1-(1-{[2-Methoxy-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.22 (s, 1H), 7.71-7.81 (m, 2H), 7.55-7.69 (m, 2H), 7.45 (d, 1H), 7.38 (s, 1H), 7.33 (dd, 3H), 4.70 (m, 1H), 4.58 (m, 1H), 4.47 (m, 1H), 4.36 (m, 1H), 3.94-4.25 (m, 5H), 3.89 (s, 3H), 3.21 (m, 4H); LC/MS m/z (M + H⁺) 531.2 (calculated for C₂₆H₂₅F₃N₄O₃S, 530.57) 249 1-(1-{[2-Methoxy-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.72-7.84 (m, 2H), 7.56-7.71 (m, 2H), 7.27-7.56 (m, 8H), 4.66 (m, 1H), 4.37-4.59 (m, 2H), 4.32 (m, 1H), 3.66-4.03 (m, 8H), 3.08 (m, 4H); LC/MS m/z (M + H⁺) 524.3 (calculated for C₂₉H₂₈F₃N₃O₃, 523.56) 250 1-(1-{[3-Chloro-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.90-8.03 (m, 3H), 7.82-7.90 (m, 2H), 7.62-7.79 (m, 3H), 7.57 (d, 1H), 4.62-4.78 (m, 2H), 4.41-4.54 (m, 1H), 4.20-4.40 (m, 3H), 3.90-4.10 (m, 3H), 3.02- 3.24 (m, 4H); LC/MS m/z (M + H⁺) 535.0 (calculated for C₂₅H₂₂ClF₃N₄O₂S, 534.99) 251 1-(1-{[3-Chloro-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.05 (s, 1H), 8.20 (s, 1H), 7.90-8.02 (m, 2H), 7.85 (s, 1H), 7.63-7.81 (m, 3H), 7.56 (d, 1H), 4.40-4.54 (m, 1H), 4.17-4.38 (m, 3H), 3.85-4.17 (m, 5H), 2.98-3.15 (m, 4H); LC/MS m/z (M + H⁺) 535.0 (calculated for C₂₅H₂₂ClF₃N₄O₂S, 534.99) 252 1-(1-{[3-Chloro-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.87-7.97 (m, 2H), 7.84 (d, 1H), 7.64-7.79 (m, 3H), 7.55 (d, 1H), 7.41-7.52 (m, 5H), 4.41 (dd, 1H), 4.21-4.34 (m, 2H), 4.17 (dd, 1H), 3.65-3.99 (m, 5H), 2.94 (m, 4H); LC/MS m/z (M + H⁺) 528.2 (calculated for C₂₈H₂₅ClF₃N₃O₂, 527.98) 253 1-{1-[(3′-Chloro-4′-fluoro-3-methylbiphenyl-4- yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.05 (s, 1H), 8.19 (d, 1H), 7.75 (dd, 1H), 7.55-7.66 (m, 2H), 7.51 (dd, 1H), 7.27-7.45 (m, 2H), 4.42 (dd, 1H), 4.21-4.34 (m, 2H), 3.95-4.21 (m, 5H), 3.88 (m, 1H), 2.94-3.15 (m, 4H), 2.46 (s, 3H); LC/MS m/z (M + H⁺) 499.0 (calculated for C₂₅H₂₄ClFN₄O₂S, 499.01) 254 1-(1-{[4′-Chloro-3-methyl-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.05 (s, 1H), 8.19 (d, 1H), 7.98 (d, 1H), 7.88 (dd, 1H), 7.71 (d, 1H), 7.63 (m, 1H), 7.57 (dd, 1 H), 7.45 (d, 1H), 4.44 (dd, 1H), 4.23-4.35 (m, 2H), 3.85- 4.23 (m, 6H), 2.96-3.19 (m, 4H), 2.48 (s, 3H); LC/MS m/z (M + H⁺) 549.2 (calculated for C₂₆H₂₄ClF₃N₄O₂S, 549.02) 255 1-{1-[(3′-Chloro-4′-fluoro-3-methylbiphenyl-4- yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.75 (dd, 1H), 7.28-7.65 (m, 10H), 4.38 (dd, 1H), 4.16-4.29 (m, 2H), 4.10(m, 1H), 3.60-3.95 (m, 5H), 2.91 (m, 4H), 2.45 (s, 3 H); LC/MS m/z (M + H⁺) 492.1 (calculated for C₂₈H₂₇ClFN₃O₂, 492.00) 256 1-(1-{[4′-Chloro-3-methyl-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (m, 1H), 7.87 (dd, 1H), 7.71 (d, 1H), 7.62 (m, 1H), 7.56 (m, 1H), 7.38-7.52 (m, 6H), 4.39 (dd, 1H), 4.16-4.28 (m, 2H), 4.11 (m, 1H), 3.63-3.93 (m, 5H), 2.91 (m, 4H), 2.47 (s, 3H); LC/MS m/z (M + H⁺) 542.1 (calculated for C₂₉H₂₇ClF₃N₃O₂, 542.01) 257 1-{1-[(3′-Chloro-4′-fluoro-2-methylbiphenyl-4- yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.20 (s, 1H), 7.49-7.67 (m, 2H), 7.44 (dd, 1H), 7.20-7.37 (m, 3H), 4.63 (m, 1H), 4.37-4.56 (m, 2H), 4.31 (m, 1H), 3.84-4.19 (m, 5H), 3.12 (m, 4H), 2.30(s, 3H); LC/MS m/z (M + H⁺) 499.0 (calculated for C₂₅H₂₄ClFN₄O₂S, 499.01) 258 1-(1-{[4′-Chloro-2-methyl-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.20 (s, 1H), 7.66-7.76 (m, 2H), 7.51-7.65 (m, 3H), 7.36 (d, 1H), 4.63 (m, 1H), 4.37-4.56 (m, 2H), 4.29 (m, 1H), 3.84-4.21 (m, 5H), 3.09 (m, 4H), 2.30(s, 3H); LC/MS m/z (M + H⁺) 549.2 (calculated for C₂₆H₂₄ClF₃N₄O₂S, 549.02) 259 1-{1-[(3′-Chloro-4′-fluoro-2-methylbiphenyl-4- yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.59 (m, 1H), 7.40-7.57 (m, 7H), 7.23-7.39 (m, 3H), 4.65 (m, 1H), 4.37-4.58 (m, 2H), 4.32 (m, 1H), 3.67-4.05 (m, 5H), 3.11 (m, 4H), 2.30 (s, 3H); LC/MS m/z (M + H⁺) 492.1 (calculated for C₂₈H₂₇ClFN₃O₂, 492.00) 260 1-(1-{[4′-Chloro-2-methyl-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.70-7.80 (m, 3H), 7.42-7.68 (m, 7H), 7.35 (d, 1H), 4.63 (m, 1H), 4.34-4.55 (m, 2H), 4.28 (m, 1H), 3.67-3.98 (m, 5H), 3.02 (m, 4H), 2.30 (s, 3H); LC/MS m/z (M + H⁺) 542.1 (calculated for C₂₉H₂₇ClF₃N₃O₂, 542.01) 261 1-{1-[(3′-Chloro-4′-fluoro-2-methoxybiphenyl-4- yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.20 (s, 1H), 7.61 (d, 1H), 7.20-7.50 (m, 5H), 4.67 (m, 1H), 4.55 (m, 1H), 4.43 (m, 1H), 4.31 (m, 1H), 3.90-4.25 (m, 5H), 3.90 (s, 3H), 3.11 (m, 4H); LC/MS m/z (M + H⁺) 515.1 (calculated for C₂₅H₂₄ClFN₄O₃S, 515.01) 262 1-(1-{[4′-Chloro-2-methoxy-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.17 (s, 1H), 7.88 (s, 1H), 7.74 (dd, 1H), 7.66 (d, 1H), 7.45 (d, 1H), 7.38 (m, 1H), 7.33 (dd, 1H), 4.65 (m, 1H), 4.33-4.56 (m, 2H), 4.26 (m, 1H), 3.89-4.12 (m, 5H), 3.89 (s, 3H), 2.97 (m, 4H); LC/MS m/z (M + H⁺) 565.0 (calculated for C₂₆H₂₄ClF₃N₄O₃S, 565.02) 263 1-{1-[(3′-Chloro-4′-fluoro-2-methoxybiphenyl-4- yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.61 (dd, 1H), 7.38-7.57 (m, 7H), 7.35 (d, 1H), 7.23-7.33 (m, 2H), 4.65 (m, 1H) 4.36-4.57 (m, 2H), 4.30 (m, 1H), 3.88 (s, 3H), 3.67-3.97 (m, 5H), 3.05 (m, 4H); LC/MS m/z (M + H⁺) 508.0 (calculated for C₂₈H₂₇ClFN₃O₃, 508.00) 264 1-(1-{[4′-Chloro-2-methoxy-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.88 (d, 1H), 7.74 (dd, 1H), 7.66 (d, 1H), 7.42-7.57 (m, 6H), 7.38 (m, 1H), 7.32 (dd, 1H), 4.58-4.69 (m, 1H), 4.36-4.58 (m, 2H), 4.20-4.33 (m, 1H), 3.89 (s, 3H), 3.60-4.04 (m, 5H), 3.03 (m, 4 H); LC/MS m/z (M + H⁺) 558.2 (calculated for C₂₉H₂₇ClF₃N₃O₃, 558.01) 265 1-{1-[(3,3′-Dichloro-4′-fluorobiphenyl-4-yl)carbonyl]azetidin- 3-yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.05 (s, 1H), 8.18 (s, 1H), 7.77-7.83 (m, 2H), 7.68 (dd, 1H), 7.58-7.67 (m, 1H), 7.53 (d, 1H), 7.36 (t, 1H), 4.42 (dd, 1H), 4.22-4.35 (m, 2H), 4.18 (dd, 1H), 3.80-4.13 (m, 5H), 2.90-3.11 (m, 4H); LC/MS m/z (M + H⁺) 519.0 (calculated for C₂₄H₂₁Cl₂FN₄O₂S, 519.43) 266 1-(1-{[3,4′-Dichloro-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.05 (s, 1H), 8.18 (s, 1H), 8.01 (m, 1H), 7.81-7.98 (m, 2H), 7.74 (d, 2H), 7.56 (d, 1H), 4.36- 4.49 (dd, 1H), 4.22-4.35 (m, 2H), 4.19 (dd, 1H), 3.80-4.13 (m, 5H), 2.90-3.11 (m, 4H); LC/MS m/z (M + H⁺) 569.0 (calculated for C₂₅H₂₁Cl₂F₃N₄O₂S, 569.44) 267 1-{1-[(3,3′-Dichloro-4′-fluorobiphenyl-4-yl)carbonyl]azetidin- 3-yl}-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.77-7.84 (m, 2H), 7.58-7.71 (m, 2H), 7.42-7.57 (m, 6H), 7.36 (t, 1H), 4.42 (dd, 1H) 4.13- 4.34 (m, 3H), 3.62-4.01 (m, 5H), 2.98 (m, 4H); LC/MS m/z (M + H⁺) 512.1 (calculated for C₂₇H₂₄Cl₂FN₃O₂, 512.42) 268 1-(1-{[3,4′-Dichloro-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 8.01 (d, 1H), 7.90 (dd, 1H), 7.85 (d, 1H), 7.74 (d, 2H), 7.56 (d, 1H), 7.41-7.53 (m, 5H), 4.43 (dd, 1H), 4.14-4.35 (m, 3H), 3.63-4.04 (m, 5H), 2.99 (m, 4H); LC/MS m/z (M + H⁺) 562.0 (calculated for C₂₈H₂₄Cl₂F₃N₃O₂, 562.42) 488 1-{1-[(3-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-4-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.22 (s, 1H), 7.30-7.71 (m, 8H), 3.92-4.57 (m, 9H) 3.11-3.29 (m, 4H), 2.46(s, 3H); LC/MS m/z (M + H⁺) 447.1 (calculated for C₂₅H₂₆N₄O₂S, 446.58) 1070 1-(1-{[2-Fluoro-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 518.9 1102 1-(1-{[2-Chloro-3′-(trifluoromethyl)biphenyl-4- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 434.9

Example 7

A. 2,2,2-Trifluoro-1-[4-(thiazole-2-carbonyl)-piperazin-1-yl]-ethanone, 7a

To a solution of compound 1d (5 g, 0.027 mol) in DMF (50 mL) and DIPEA (19.5 mL, 0.11 mol) was added compound 5c (3.3 g, 0.0255 mol) and HATU (12.6 g, 0.033 mol). The reaction was stirred for 4 h then poured into water and extracted with EtOAc. The organic portions were washed with water and brine, and dried over MgSO₄. The solvent was evaporated in vacuo. The residue was passed through a silica gel column (30-10%: EtOAc-heptane) to give compound 7a (3.8 g). MS m/z (M+H⁺) 294.1.

B. Piperazin-1-yl-thiazol-2-yl-methanone, 7b

A solution of compound 7a (3.8 g, 0.013 mol) and K₂CO₃ (3.5 g, 0.026 mol) in MeOH (40 mL) and water (10 mL), was stirred for 4 h. The solid was collected by filtration and the solvent evaporated in vacuo to give compound 7b (6.12 g). MS m/z (M+H⁺) 198.1.

C. 3-[4-(Thiazole-2-carbonyl)-piperazin-1-yl]-azetidine-1-carboxylic acid tert-butyl ester, 7c

A solution of compound 7b (6.1 g, 0.031 mol) and (5.1 g, 0.03 mol) compound 4a in MeOH (30 mL) was stirred for 15 min Decaborane (1 g, 0.008 mol) was added and the reaction was stirred for 18 h. The solvent was evaporated in vacuo. The residue was used without further purification for the next step. MS m/z (M+H⁺) 353.1.

D. (4-Azetidin-3-yl-piperazin-1-yl)-thiazol-2-ylmethanone, 5e

To a solution of compound 7c in CH₂Cl₂ (100 mL) was added TFA (30 mL). The reaction was stirred for 3.5 h and the solvent was evaporated in vacuo. The residue was purified by reverse phase preparative HPLC to give compound 5e (5.15 g). MS m/z (M+H⁺) 253.1.

E. 1-{1-[3-(4-Chlorophenyl)propanoyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 269

To a solution of compound 5e (150 mg, 0.52 mmol) in DMF (5 mL) and DIPEA (0.40 mL, 2.2 mmol) was added compound 7d (125 mg, 0.067 mmol), and HATU (0.25 g, 0.067 mmol). The reaction was stirred for 4 h, then poured into water and extracted with EtOAc. The combined extracts were concentrated in vacuo. The resultant residue was purified by reverse phase HPLC to give compound 269 (20.2 mg). LC/MS m/z (M+H⁺) 419.15 (calculated for C₂₀H₂₃ClN₄O₂S, 418.95).

Following the procedure described above for Example 7 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared.

Cpd Cpd Name and Data 270 1-{1-[3-(4-Bromophenyl)propanoyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + 2H⁺) 465.05 (calculated for C₂₀H₂₃BrN₄O₂S, 463.40) 271 1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{3-[4- (trifluoromethyl)phenyl]propanoyl}azetidin-3-yl)piperazine. LC/MS m/z (M + H⁺) 453.15 (calculated for C₂₁H₂₃F₃N₄O₂S, 452.50) 272 1-{1-[3-(3-Chlorophenyl)propanoyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 419.17 (calculated for C₂₀H₂₃ClN₄O₂S, 418.95) 273 1-{1-[3-(2-Chlorophenyl)propanoyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine. ¹H NMR (300 MHz, MeOD): δ 8.0 (d, 1H), 7.9 (d, 2H), 4.7 (bm, 2H), 4.4 (m, 2H), 4.3-4.1 (m, 2H), 4.0 (bm, 2H), 3.25 (m, 5H), 3.0 (m, 2H), 2.5 (m, 2H) LC/MS m/z (M + H⁺) 419.16 (calculated for C₂₀H₂₃ClN₄O₂S, 418.95) 274 1-{1-[3-(2,6-Dichlorophenyl)propanoyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine. ¹H NMR (300 MHz, MeOD): δ 8 (d, 1H), 7.9 (d, 1H), 7.4 (ar, 2H), 7.2 (m, 1H), 4.75 (m, 2H), 4.5-4.1 (m, 5H), 4.0 (m, 3H), 3.2 (m, 5H), 2.4 (m, 3H) LC/MS m/z (M + 2H⁺) 455.10 (calculated for C₂₀H₂₂Cl₂N₄O₂S, 453.39) 275 1-{1-[3-(3,4-Difluorophenyl)propanoyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 421.19 (calculated for C₂₀H₂₂F₂N₄O₂S, 420.48) 276 1-{1-[3-(4-Methylphenyl)propanoyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 399.23 (calculated for C₂₁H₂₆N₄O₂S, 398.53) 277 1-{1-[3-(4-Methoxyphenyl)propanoyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine3 LC/MS m/z (M + H⁺) 415.23 (calculated for C₂₁H₂₆N₄O₃S, 414.53) 278 1-(1-{3-[3,5-Bis(trifluoromethyl)phenyl]propanoyl}azetidin-3- yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 521.14 (calculated for C₂₂H₂₂F₆N₄O₂S, 520.50) 279 1-[1-(3-Naphthalen-1-ylpropanoyl)azetidin-3-yl]-4-(1,3-thiazol- 2-ylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 435.22 (calculated for C₂₄H₂₆N₄O₂S, 434.56) 280 1-{1-[3-(4-Phenoxyphenyl)propanoyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 477.20 (calculated for C₂₆H₂₈N₄O₃S, 476.60) 281 1-{1-[3-(3,4-Dichlorophenyl)propanoyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine. ¹H NMR (300 MHz, MeOD) d 8.0 (ar, 1H), 7.9 (ar, 1H), 7.4 (m, 2H), 7.2 (m, 1H), 4.4 (dd, 1H), 4.3-4.2 (m, 2H), 4.1 (m, 1H), 3.9 (m, 1H), 3.3 (m, 3H), 3.2 (m, 4H), 3.0 (bs, 1H), 2.9 (m, 2H), 2.5 (m, 2H) LC/MS m/z (M + 2H⁺) 455.10 (calculated for C₂₀H₂₂Cl₂N₄O₂S, 453.39) 282 1-{1-[3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)propanoyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine. ¹H NMR (300 MHz, MeOD): δ 7.9 (ar, 1H), 7.7 (ar, 1H), 7.13 (ar, 1H), 7.0 (ar, 1H), 6.9 (ar, 1H), 4.2-4.1 (m, 2H), 4.1-4.0 (m, 1H), 3.9, (bs, 1H), 3.8 (m, 1H), 3.2 (m, 2H), 3.11 (m, 4H), 2.7 (t, 2H), 2.3 (t, 2H), 1.5 (s, 4H), 1.1 (dd, 12H). LC/MS m/z (M + H⁺) 495.24 (calculated for C₂₈H₃₈N₄O₂S, 494.70) 283 1-(1,3-Thiazol-2-ylcarbonyl)-4-{l-[(2E)-3-{4- [(trifluoromethyl)sulfanyl]phenyl}prop-2-enoyl]azetidin-3- yl}piperazine LC/MS m/z (M + H⁺) 483.18 (calculated for C₂₁H₂₁F₃N₄O₂S₂, 482.55) 284 1-{1-[(3-Chlorophenoxy)acetyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 421.12 (calculated for C₁₉H₂₁ClN₄O₃S, 420.92) 285 1-{1-[(2-Chlorophenoxy)acetyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 421.12 (calculated for C₁₉H₂₁ClN₄O₃S, 420.92) 286 1-{1-[3-(2-Bromophenyl)propanoyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine. LC/MS m/z (M + 2H⁺) 465.07 (calculated for C₂₀H₂₃BrN₄O₂S, 463.40) 287 1-(1-{3-[4-(3,4-Dimethyl-1H-pyrazol-1- yl)phenyl]propanoyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 479.29 (calculated for C₂₅H₃₀N₆O₂S, 478.62) 288 1-{1-[(2,4-Dichlorophenoxy)acetyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine. LC/MS m/z (M + 2H⁺) 457.13 (calculated for C₁₉H₂₀Cl₂N₄O₃S, 455.37) 289 1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[4- (trifluoromethoxy)phenoxy]acetyl}azetidin-3-yl)piperazine. LC/MS m/z (M + H⁺) 471.16 (calculated for C₂₀H₂₁F₃N₄O₄S, 470.47) 290 N-Cyclopropyl-4-(3-oxo-3-{3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1- yl}propyl)benzenesulfonamide. ¹H NMR (300 MHz, MeOD) d 8.0 (d, 1H); 7.9 (d, 1H); 7.4 (m, 4H); 4.7 (bs, 2H), 4.4-4.1 (m, 3H), 4.1-3.9 (m, 3H), 3.8 (m, 1H), 3.1 (m, 3H), 3.0 (t, 2H), 2.5 (t, 2H), 2.1 m, 1H), 0.5 (m, 4H) LC/MS m/z (M + H⁺) 504.20 (calculated for C₂₃H₂₉N₅O₄S₂, 503.65) 291 N-(Cyclohexylmethyl)-N-methyl-4-(3-oxo-3-{3-[4-(1,3-thiazol- 2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}propyl)aniline. ¹H NMR (300 MHz, MeOD): δ 8.0 (d, 1H), 7.9 (d, 1H), 7.5 (m, 4H), 4.4 (bm, 2H), 4.25-4.0 (m, 4H), 3.8 (m, 1H), 3.4 (d, 2H), 3.2 (s, m, 3H), 3.1 (bs, 3H), 3.0 (t, 2H), 2.5 (t, 2H), 1.7 (m, 5H), 1.1 (m, 5H) LC/MS m/z (M + H⁺) 510.32 (calculated for C₂₈H₃₉N₅O₂S, 509.72) 292 1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({[4- (trifluoromethyl)phenyl]sulfanyl}acetyl)azetidin-3- yl]piperazine LC/MS m/z (M + H⁺) 471.18 (calculated for C₂₀H₂₁F₃N₄O₂S₂, 470.54) 293 l-[1-(1-Benzothiophen-2-ylcarbonyl)azetidin-3-yl]-4-(1,3- thiazol-2-ylcarbonyl)piperazine LC/MS m/z (M + H⁺) 413.20 (calculated for C₂₀H₂₀N₄O₂S₂, 412.54) 294 1-{1-[3-(4-Ethoxyphenyl)propanoyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 429.27 (calculated for C₂₂H₂₈N₄O₃S, 428.56) 295 1-{1-[(2E)-3-(2-Chlorophenyl)prop-2-enoyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 417.0 (calculated for C₂₀H₂₁ClN₄O₂S, 416.93) 296 1-{1-[(2E)-3-(2-Bromophenyl)prop-2-enoyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine. LC/MS m/z (M + H⁺) 462.9 (calculated for C₂₀H₂₁BrN₄O₂S, 461.38) 297 3-Naphthalen-2-yl-1-{3-[4-(thiazole-2-carbonyl)-piperazin-1- yl]-azetidin-1-yl}-propenone LC/MS m/z (M + H⁺) 433.29 (calculated for C₂₄H₂₄N₄O₂S, 432.55)

Example 8

A. 4-(1-Benzhydryl-azetidin-3-yl)-piperazine-1-carboxylic acid benzyl ester, 8b

To a solution of compound 8a (1.4 g, 6.3 mmol) and compound 1e (2 g, 6.3 mmol) in CH₃CN (30 mL) was added DIPEA (1.5 mL, 8.1 mmol) at room temperature. The mixture was refluxed for 18 h. The solvent was removed under reduced pressure and the residue was partitioned between CHCl₃ and water. The organic layer was dried over K₂CO₃, filtered, and concentrated to give crude compound 8b (2.65 g). MS m/z (M+H⁺) 442.

B. 4-Azetidin-3-yl-piperazine-1-carboxylic acid benzyl ester, 8c

To a solution of compound 8b (3.4 g, 7.7 mmol) in CH₂Cl₂ was added 1-chloroethyl chloroformate (2.5 mL, 23.1 mmol) at 0° C. under a N₂ atmosphere. The ice bath was removed and the reaction stirred for 2 h. The organic phase was concentrated under reduced pressure, and MeOH was added to the resultant residue. The reaction was refluxed for 2 h at which time the solvent was removed under reduced pressure. The residue was partitioned between chloroform and aqueous HCl (1N). The aqueous layer was separated, made basic with aqueous NaOH (3N), and extracted with chloroform. The organic layer was then dried (K₂CO₃), filtered and concentrated to afford compound 8c (2.65 g). MS m/z (M+H⁺) 276.

C. 4-[1-(Biphenyl-4-carbonyl)-azetidin-3-yl]-piperazine-1-carboxylic acid benzyl ester, 8e

To a solution of compound 8c (2.6 g, 9.4 mmol), compound 8d (1.87 g, 9.4 mmol), and DIPEA (2.43 g, 18.9 mmol) in acetonitrile was added HBTU (4.6 g, 12.3 mmol). The reaction was stirred for 18 h at which time the solvent was removed under reduced pressure and the crude product purified by reverse phase HPLC. Lyophilization provided compound 8e (1.74 g). MS m/z (M+H⁺) 456.2.

D. Biphenyl-4-yl-(3-piperazin-1-yl-azetidin-1-yl)-methanone, 8f

A mixture of compound 8e (1.7 g, 2.9 mmol), and 10% Palladium on carbon (300 mg) was hydrogenated (50 psi hydrogen gas) using a Parr apparatus for 18 h. The catalyst was removed by filtration, and the solvent concentrated under reduced pressure to afford crude compound 8f (1.5 g). MS m/z (M+H⁺) 322.

E. 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(4-fluorophenyl)-carbonyl]piperazine, Cpd 299

To a solution of compound 8f (100 mg, 0.3 mmol), compound 8g (44 mg, 0.31 mmol), and DIPEA (80 mg, 0.6 mmol) in dimethylformamide was added HBTU (141 mg, 0.37 mmol). After stirring for 18 h, the reaction was purified by preparative reverse phase HPLC to yield compound 299. ¹H NMR (400 MHz, MeOD): δ 7.93-8.03 (m, 1H), 7.61-7.71 (m, 4H), 7.54-7.61 (m, 2H), 7.43-7.50 (m, 2H), 7.35-7.43 (m, 2H), 7.27-7.35 (m, 1H), 7.07-7.20 (m, 2H), 4.55-4.67 (m, 1H), 4.43-4.53 (m, 1H), 4.32-4.43 (m, 1H), 4.19-4.32 (m, 1H), 3.89-4.00 (m, 1H), 3.66-3.89 (m, 4H), 3.08 (br. s., 4H); MS m/z (M+H⁺) 444.2 (calculated for C₂₇H₂₆FN₃O₂, 443.53).

Following the procedure described above for Example 8 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 300 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(2- fluorophenyl)carbonyl]piperazine MS m/z (M + H⁺) 444.2 (calculated for C₂₇H₂₆FN₃O₂, 443.53) 301 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(thiophen-3- ylcarbonyl)piperazine MS m/z (M + H⁺) 432.1 (calculated for C₂₅H₂₅N₃O₂S, 431.56) 302 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1H-pyrrol-2- ylcarbonyl)piperazine MS m/z (M + 2H⁺) 416.2 (calculated for C₂₅H₂₆N₄O₂, 414.51) 303 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4- (cyclopropylcarbonyl)piperazine MS m/z (M + H⁺) 390.23 (calculated for C₂₄H₂₇N₄O₂, 389.5) 304 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(3- fluorophenyl)carbonyl]piperazine MS m/z (M + H⁺) 444.2 (calculated for C₂₇H₂₆FN₃O₂, 443.53) 305 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,3-oxazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 417.2 (calculated for C₂₄H₂₄N₄O₃, 416.48) 306 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,2,3- thiadiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 434.1 (calculated for C₂₃H₂₃N₅O₂S, 433.54) 307 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(isoxazol-5- ylcarbonyl)piperazine MS m/z (M + H⁺) 417.2 (calculated for C₂₄H₂₄N₄O₃, 416.48) 308 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,2,5- oxadiazol-3-ylcarbonyl)piperazine MS m/z (M + H⁺) 418.2 (calculated for C₂₃H₂₃N₅O₃, 417.47) 309 5-({4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]piperazin-1- yl}carbonyl)thiophene-3-carbonitrile MS m/z (M + H⁺) 457.2 (calculated for C₂₆H₂₄N₄O₂S, 456.57) 310 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(isothiazol-5- ylcarbonyl)piperazine ¹H NMR (400 MHz, MeOD): δ 8.44 (s, 1H), 7.65 (s, 4H), 7.53-7.58 (m, 2H), 7.47 (d, J = 1.71 Hz, 1H), 7.34-7.40 (m, 2H), 7.26-7.32 (m, 1H), 4.49-4.60 (m, 1H), 4.37-4.49 (m, 1H), 4.27-4.37 (m, 1H), 4.15-4.27 (m, 1H), 3.72-3.88 (m, 5H), 2.92-3.02 (m, 4H); MS m/z (M + H⁺) 433.2 (calculated for C₂₄H₂₄N₄O₂S, 432.55) 311 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1H-pyrrol-3- ylcarbonyl)piperazine ¹H NMR (400 MHz, MeOD): δ 7.66 (s, 4H), 7.56-7.59 (m, 1H), 7.54-7.56 (m, 1H), 7.35-7.41 (m, 2H), 7.26-7.33 (m, 1H), 7.08-7.15 (m, 1H), 6.64-6.75 (m, 1H), 6.24-6.31 (m, 1H), 4.54-4.64 (m, 1H), 4.43-4.51 (m, 1H), 4.32-4 .41 (m, 1H), 4.20-4.28 (m, 1H), 3.85-3.97 (m, 5H), 3.06 (br. s., 4H); MS m/z (M + H⁺) 415.2 (calculated for C₂₅H₂₆N₄O₂, 414.51) 312 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(5- chlorofuran-2-yl)carbonyl]piperazine ¹H NMR (400 MHz, MeOD): δ 7.66 (s, 4H), 7.54-7.59 (m, 2H), 7.38 (d, J = 7.58 Hz, 2H), 7.26-7.33 (m, 1H), 7.05 (d, J = 3.67 Hz, 1H), 6.42 (d, J = 3.42 Hz, 1H), 4.50-4.63 (m, 1H), 4.40-4.48 (m, 1H), 4.28-4.39 (m, 1H), 4.17-4.28 (m, 1H), 3.87-3.97 (m, 4H), 3.78-3.87 (m, 1H), 2.97-3.07 (m, 4H); MS m/z (M + H⁺) 450.1 (calculated for C₂₅H₂₄ClN₃O₃, 449.94) 480 N-[4-({4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]piperazin- 1-yl}carbonyl)-l,3-thiazol-2-yl]acetamide MS m/z (M + H⁺) 490.2 1478 2-({4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]piperazin-1- yl}carbonyl)pyrimidine MS m/z (M + H⁺) 428.0 1398 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4- (cyclopentylcarbonyl)piperazine MS m/z (M + H⁺) 418.2 1465 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(5- methylisoxazol-3-yl)carbonyl]piperazine MS m/z (M + H⁺) 431.3 1258 1-[1-(1,3-Oxazol-4-ylcarbonyl)azetidin-3-yl]-4-{[3′- (trifluoromethyl)biphenyl-4-yl]carbonyl}piperazine MS m/z (M + H⁺) 485.0 1262 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(isoxazol-3- ylcarbonyl)piperazine MS m/z (M + H⁺) 417.1 1222 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,3-oxazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 417.0 1269 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1H-1,2,3- triazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 417.0 1256 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-[(2,2- difluorocyclopropyl)carbonyl]piperazine MS m/z (M + H⁺) 426.0 1310 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1H-pyrazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 416.2 1140 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(furan-3- ylcarbonyl)piperazine MS m/z (M + H⁺) 416.2 1232 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4- (cyclobutylcarbonyl)piperazine MS m/z (M + H⁺) 404.2 1308 3-({4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]piperazin-1- yl}carbonyl)-1H-indole MS m/z (M + H⁺) 465.3 1324 1-(1H-Pyrrol-3-ylcarbonyl)-4-(1-{[3′- (trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z (M + H⁺) 481.0 1325 1-(1H-Pyrrol-2-ylcarbonyl)-4-(1-{[3′- (trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z (M + H⁺) 483.1 186-A 1-[(D₅)Phenylcarbonyl]-4-(1-{[3′-(trifluoromethyl)biphenyl- 4-yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 499.4 1169 1-(1,3-Oxazol-5-ylcarbonyl)-4-(1-{[3′- (trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z (M + H⁺) 485.0 1335 1-[(5-Bromofuran-2-yl)carbonyl]-4-(1-{[3′- (trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z (M + H⁺) 560.0/562.0 1087 1-[(4-Bromothiophen-2-yl)carbonyl]-4-(1-{[3′- (trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z (M + H⁺) 576.0/578.0 1078 1-[(5-Chlorofuran-2-yl)carbonyl]-4-(1-{[3′- (trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z (M + H⁺) 518.2 1118 1-(Isoxazol-5-ylcarbonyl)-4-(1-{[3′- (trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z (M + H⁺) 485.1 1336 1-[(5-Fluorothiophen-2-yl)carbonyl]-4-(1-{[3′- (trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z (M + H⁺) 519.2 1145 1-(Isoxazol-3-ylcarbonyl)-4-(1-{[3′- (trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z (M + H⁺) 485.2 1143 1-[(5-Chlorothiophen-2-yl)carbonyl]-4-(1-{[3′- (trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z (M + H⁺) 535.2 1085 1-(1,3-Oxazol-2-ylcarbonyl)-4-(1-{[3′- (trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z (M + H⁺) 485.1 1112 1-[(2,2-Difluorocyclopropyl)carbonyl]-4-(1-{[3′- (trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z (M + H⁺) 494.2 1094 1-(1,3-Oxazol-4-ylcarbonyl)-4-(1-{[3′- (trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z (M + H⁺) 485.2 1057 1-(Cyclopropylcarbonyl)-4-(1-{[3′-(trifluoromethyl)biphenyl- 4-yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 458.3 1217 1-[(2-Methyl-l,3-thiazol-4-yl)carbonyl]-4-(1-{[3′- (trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine MS m/z (M + H⁺) 516.3 1423 5-[(3-{4-[(5-Chlorothiophen-2-yl)carbonyl]piperazin-1- yl}azetidin-1-yl)carbonyl]-1-(4-fluorophenyl)-1H-indole MS m/z (M + H⁺) 523.2 1424 1-(4-Fluorophenyl)-5-[(3-{4-[(3- fluorophenyl)carbonyl]piperazin-1-yl}azetidin-1- yl)carbonyl]-1H-indole MS m/z (M + H⁺) 501.2 1425 5-[(3-{4-[(5-Chlorofuran-2-yl)carbonyl]piperazin-1- yl}azetidin-1-yl)carbonyl]-1-(4-fluorophenyl)-1H-indole MS m/z (M + H⁺) 507.1 1426 1-(4-Fluorophenyl)-5-({3-[4-(1,3-oxazol-2- ylcarbonyl)piperazin-1-yl] azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 474.1 567-A 1-(4-Fluorophenyl)-5-[(3-{4- [(~2~H_5_)phenylcarbonyl]piperazin-1-yl} azetidin-1- yl)carbonyl]-l H-indole MS m/z (M + H⁺) 488.1 1427 1-(4-Fluorophenyl)-5-[(3-{4-[(5-fluorothiophen-2- yl)carbonyl]piperazin-1-yl}azetidin-1-yl)carbonyl]-1H-indole MS m/z (M + H⁺) 507.1 1428 1-(4-Fluorophenyl)-5-({3-[4-(1,3-oxazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 474.1 1429 1-(4-Fluorophenyl)-5-({3-[4-(1,3-oxazol-5- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 474.1

Example 9

A. 4-(Thiazole-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester, 9a

To a solution of compound 5c (2.0 g, 15.50 mmol), compound 1a (3.2 g, 17.20 mmol), and Et₃N (8.6 mL, 61.2 mmol) in CH₂Cl₂ (100 mL) was added HATU (6.5 g, 17.1 mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was then diluted with CH₂Cl₂ and washed with aq. NaHCO₃. The organic phase was dried over Na₂SO₄, filtered, and concentrated. Purification by flash column chromatography (silica gel, 30% EtOAc/heptane) gave compound 9a (4.0 g).

B. Piperazin-1-yl-thiazol-2-yl-methanone trifluoroacetic acid salt, 9b

To a solution of compound 9a (3.5 g, 11.78 mmol) in CH₂Cl₂ (40 mL) was added TFA (10 mL). The reaction mixture was stirred at room temperature for 2 h. It was then concentrated to give compound 9b, which was used in the next reaction without further purification.

C. 3-[4-(Thiazole-2-carbonyl)-piperazin-1-yl]-azetidine-1-carboxylic acid tert-butyl ester, 7c

To a solution of compound 9b (11.78 mmol) and compound 4a (2.2 g, 12.87 mmol) in 1,2-DCE (35 mL) and acetic acid (2 mL) was added Na(OAc)₃BH (2.75 g, 12.97 mmol). The reaction was stirred at room temperature for 5 h. To the reaction mixture was added aq. NaHCO₃, and the resultant mixture was extracted with CH₂Cl₂. The organic layer was dried over Na₂SO₄ and concentrated. Purification by flash column chromatography (silica gel, 80% EtOAc/heptane) gave compound 7c (3.78 g).

D. (4-Azetidin-3-yl-piperazin-1-yl)-thiazol-2-yl-methanone, 5e

To a solution of compound 7c (1.2 g, 3.41 mmol) in CH₂Cl₂ (12 mL) was added TFA (3 mL). The reaction mixture was stirred at room temperature for 4.5 h, concentrated, and to the resulting residue was added aq. NaHCO₃. The mixture was extracted with 2% MeOH/CH₂Cl₂ (3×). The organic solution was dried over Na₂SO₄ and concentrated to give compound 5e, which was used in the next reaction without further purification.

D. 1-{1-[(5-Bromonaphthalen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 313

To a solution of compound 5e (63 mg, 0.25 mmol), compound 9c (95 mg, 0.38 mmol), and Et₃N (0.14 mL, 1.01 mmol) in CH₂Cl₂ (3 mL) was added HATU (143 mg, 0.38 mmol). The reaction mixture was stirred at room temperature for 18 h, then diluted with diethyl ether and washed with aq. NaHCO₃ and aq. NaCl. The organic layer was dried over Na₂SO₄ and concentrated. Purification by flash column chromatography (silica gel, 3% MeOH/CH₂Cl₂) gave compound 313. ¹H NMR (400 MHz, CD₃OD): δ 8.28 (d, J=9 Hz, 1H), 8.14 (d, J=1.6 Hz, 1H), 7.88-7.85 (m, 3H), 7.81 (d, J=8.4 Hz, 1H), 7.54 (d, J=3 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 4.53 (bs, 1H), 4.45 (bs, 1H), 4.34 (m, 2H), 4.26 (m, 1H), 4.16 (m, 1H), 3.95-3.80 (m, 2H), 3.28 (m, 1H), 2.60-2.40 (m, 4H). MS m/z (M+H⁺) 485/487.

Following the procedure described above for Example 9 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 314 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-2-[4-(trifluoromethyl)phenyl]- 1,3-benzoxazole ¹H NMR (400 MHz, CD₃OD): δ 8.40 (d, J = 7.8 Hz, 1H), 7.95 (s, 1H), 7.88 (d, J = 3 Hz, 1H), 7.83-7.80 (m, 2H), 7.69 (d, J = 8 Hz, 1H), 7.55 (d, J = 3 Hz, 1H), 4.53 (m, 1H), 4.45-4.25 (m, 4H), 4.16 (m, 1H), 3.95-3.80 (m, 2H), 3.27 (m, 1H), 2.60-2.40 (m, 4H). MS m/z (M + H⁺) 542 315 6-Bromo-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 475/477 316 1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[5-(trifluoromethyl)-1- benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (400 MHz, CD₃OD): δ 8.13 (s, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 3 Hz, 1H), 7.75 (s, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 3 Hz, 1H), 4.62-4.40 (m, 4H), 4.31 (m, 1H), 4.16 (m, 1H), 3.35 (m, 1H), 2.60-2.40 (m, 4H). MS m/z (M + H⁺) 481 317 2-Phenyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole ¹H NMR (400 MHz, CD₃OD): δ 8.26 (m, 2H), 8.00 (s, 1H), 7.88 (d, J = 3 Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.60-7.52 (m, 4H), 4.60-4.40 (m, 2H), 4.38 (m,1H), 4.28 (m, 2H), 4.15 (m, 1H), 3.86 (m, 2H), 3.27 (m, 1H), 2.50 (m, 4H). MS m/z (M + H⁺) 474 318 2-Phenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole ¹H NMR (400 MHz, CD₃OD): δ 8.28 (m, 2H), 7.92 (s, 1H), 7.88 (d, J = 3.2 Hz, 1H), 7.79 (d, J = 8 Hz, 1H), 7.66 (d, J = 8 Hz, 1H), 4.60-4.20 (m, 5H), 4.15 (m, 1H), 3.86 (m, 2H), 3.28 (m, 1H), 2.50 (m, 4H). MS m/z (M + H⁺) 474 319 tert-Butyl 6-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-3,4-dihydroisoquinoline-2(1H)- carboxylate, ¹H NMR (CDCl₃): δ 7.44-7.39 (m, 7H), 7.13 (d, J = 0.02, 1H), 4.59 (s, 2H), 4.27 (m, 2H), 4.15 (m, 1H), 4.06 (m, 1H), 3.90 (m, 1H), 3.74 (m, 1H), 3.65 (m, 2H), 3.46 (m, 2H), 3.22 (m, 1H), 2.85 (m, 2H), 2.27-2.23 (m, 4H), 1.49 (s, 9H) MS m/z 405.0 (M-Boc), 449.0 (M-Bu-t), 527 (M + Na), 1009.2 (2M + H) 320 1-{1-[(4,5-Dibromothiophen-2-yl)carbonyl]azetidin-3-yl}- 4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 511.8, 513.8, 514.8 321 1-{1-[(5-Benzylthiophen-2-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine, ¹H NMR (CDCl₃): δ 7.42-7.38 (m, 5H), 7.33-7.29 (m, 3H), 7.26 (m, 3H), 6.78 (d, J = 0.01, 1H), 4.41 (m, 1H), 4.24 (m, 2H), 4.13 (s, 2H), 4.03 (m, 1H), 3.92-3.74 (m, 2H), 3.47 (m, 2H), 3.24 (m, 1H), 2.42-2.29 (m, 4H) MS m/z (M + H⁺) 446.6 322 1-{1-[(5-Bromothiophen-2-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 432.4, 434.4 832 l-Cyclohexyl-2-methyl-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 493.0 1198 1-(1-{[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazol-3-yl]carbonyl}azetidin-3-yl)-4-(1,3- thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 615.0 647 4-[4-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)piperidin-1-yl]benzonitrile MS m/z (M + H⁺) 465.1 1302 1-(1,3-Thiazol-4-ylcarbonyl)-4-[1-({4-[3- (trifluoromethyl)-1H-pyrazol-1- yl]phenyl}carbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 491.1 1261 1-{1-[(1,5-Diphenyl-1H-pyrazol-3-yl)carbonyl]azetidin-3- yl}-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 499.2 654 1-[1-(Phenoxathiin-2-ylcarbonyl)azetidin-3-yl]-4-(1,3- thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 479.1 767 9-Methyl-3-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-9H-carbazole MS m/z (M + H⁺) 460.0 822 1-(1-{[4-(Phenylsulfonyl)phenyl]carbonyl}azetidin-3-yl)- 4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 497.1 817 6-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-2,3,4,9-tetrahydro-1H- carbazole MS m/z (M + H⁺) 450.1 775 N-Benzyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)aniline MS m/z (M + H⁺) 462.3 713 N-Benzyl-3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)aniline MS m/z (M + H⁺) 462.3 1413 3-Methyl-1-[4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)phenyl]-1H-indole MS m/z (M + H⁺) 486.1 918 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,3-dihydro-2H-indol-2-one MS m/z (M + H⁺) 412.1 829 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-2,3-dihydro-1H-indole ¹H NMR (400 MHz, CD₃OD): δ 7.99 (d, 1H), 7.89 (d, 1H), 7.57 (s, 1H), 7.52 (d, J = 8. 1Hz, 1H), 7.03 (d, J = 8. 1 Hz, 1H), 4.28-4.90 (m, 6H), 4.01-4.22 (m, 3H), 3.73 (t, J = 8.2 Hz, 2H), 3.37 (br. s., 4H), 3.19 (t, J = 8.2 Hz, 2H) MS m/z (M + H⁺) 398.1 1320 1-(4-Fluorophenyl)-4-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J = 3.2 Hz, 1H), 7.50-7.57 (m, 2H), 7.42-7.48 (m, 2H), 7.38 (d, J = 3.2 Hz, 1H), 7.33 (d, J = 7.3 Hz, 1H), 7.18-7.26 (m, 3H), 6.99 (d, J = 3.2 Hz, 1H), 4.05-4.63 (m, 6H), 3.75-3.99 (m, 2H), 3.22- 3.32 (m, 1H), 2.37-2.62 (m, 4H) MS m/z (M + H⁺) 490.1 806 1-{1-[(4-Bromothiophen-2-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H) 440.0, (M + 2⁺) 442.0 718 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-2-(trifluoromethyl)-1,3- benzothiazole MS m/z 482 (M + H⁺) 1088 1-(4-Fluorophenyl)-3-methyl-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole ¹H NMR (CDCl₃,400 MHz): δ 7.98 (s, 1H), 7.88 (d, J = 3.1 Hz, 1H), 7.47-7.58 (m, 2 H), 7.38-7.47 (m, 3 H), 7.16- 7.26 (m, 2 H), 7.12 (s, 1H), 4.47-4.64 (m, 1H), 4.38 (br. s., 4 H), 4.07-4.19 (m, 1H), 3.74-3.97 (m, 2 H), 3.17-3.33 (m, 1H), 2.50 (t, J = 4.9 Hz, 4 H), 2.39 (s, 3 H). MS m/z 504 (M + H⁺) 1131 2-(3-Fluorophenyl)-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzothiazole MS m/z 508 (M + H⁺) 1054 3-Methyl-1-phenyl-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z 486 (M + H⁺) 1152 3-Methyl-1-phenyl-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z 486 (M + H⁺) 1367 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1-(3,4,5-trifluorophenyl)-1H- indole MS m/z 526 (M + H⁺) 1106 1-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indazole ^(′)H NMR (CDCl₃, 400 MHz): δ 8.27 (s, 1H), 8.12 (s, 1H), 7.88 (br. s., 1H), 7.67-7.85 (m, 2 H), 7.42-7.67 (m, 3 H), 7.36 (q, J = 8.7 Hz, 1H), 4.49-4.62 (m, 1H), 4.20-4.48 (m, 4 H), 4.05-4.20 (m, 1H), 3.84 (br. s., 2 H), 3.20-3.38 (m, 1H), 2.51 (m, 4 H). MS m/z 509 (M + H⁺) 1129 1-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indazole MS m/z 509 (M + H⁺) 1055 5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1-(3,4,5-trifluorophenyl)-1H- indole MS m/z 526 (M + H⁺) 1077 2-(3,4-Difluorophenyl)-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzoxazole MS m/z 510 (M + H⁺) 1178 2-(3,4-Difluorophenyl)-6-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzoxazole MS m/z 510 (M + H⁺) 1368 1-(3-Fluorophenyl)-3-methyl-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z 504 (M + H⁺) 1369 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1-[4- (trifluoromethoxy)phenyl]-1H-indole MS m/z 556 (M + H⁺) 1370 5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1-[4- (trifluoromethoxy)phenyl]-1H-indole MS m/z 556 (M + H⁺) 1371 1-(3,5-Difluorophenyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z 508 (M + H⁺) 1068 3-Methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1-[3- (trifluoromethoxy)phenyl]-1H-indole MS m/z 570 (M + H⁺) 1110 1-(3-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indazole MS m/z 491 (M + H⁺) 1372 l-(4-Chloro-3-fluorophenyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z 523 (M + H⁺) 1373 1-(2,5-Difluorophenyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z 508 (M + H⁺) 1090 1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indazole MS m/z 491 (M + H⁺) 1492 1-{1-[(5-Bromo-1-benzofuran-2-yl)carbonyl]azetidin-3- yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 455, 457 812 1-{1-[(5-Bromo-1-benzofuran-2-yl)carbonyl]azetidin-3- yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺)468, 470 681 7-Bromo-1-methyl-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 488, 490 723 1-{1-[(5-Bromo-4-methylthiophen-2-yl)carbonyl]azetidin- 3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 455, 457 745 1-{1-[(4-Bromo-5-methylthiophen-2-yl)carbonyl]azetidin- 3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 475, 477 1224 1-(4-Fluorophenyl)-3-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 490 1226 1-(3-Fluorophenyl)-3-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 490 1279 1-(3-Fluorophenyl)-3-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 490 1295 1-(4-Fluorophenyl)-3-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 490 1275 2-Phenyl-6-({4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3- yl]piperazin-1-yl}carbonyl)-1,3-benzoxazole MS m/z (M + H⁺) 474.1 606 7-(Biphenyl-4-ylcarbonyl)-4-[1-(phenylcarbonyl)azetidin- 3-yl]-4,7-diazaspiro[2.5]octane MS m/z (M + H⁺) 452.4 1286 7-(Biphenyl-4-ylcarbonyl)-4-[1-(1,3-thiazol-4- ylcarbonyl)azetidin-3-yl]-4,7-diazaspiro[2.5]octane MS m/z (M + H⁺) 459.3 1499 4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-7- (phenylcarbonyl)-4,7-diazaspiro[2.5]octane MS m/z (M + H⁺) 272 820 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indazole ¹H NMR (400 MHz, CDCl₃): δ 3.34-3.48 (m, 1 H), 3.89 (br. s., 3 H), 4.08-4.66 (m, 8 H), 7.55 (d, J = 8.8 Hz, 1 H), 7.62 (d, J = 3.2 Hz, 1 H), 7.66 (dd, J = 8.8, 1.5 Hz, 1 H), 7.89 (d, J = 3.2 Hz, 1 H), 8.04 (s, 1 H), 8.09 (s, 2 H) MS m/z (M + H⁺) 397.2 1277 1-(4-Fluorophenyl)-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- pyrrolo[3,2-b]pyridine ¹H NMR (400 MHz, CDCl₃): δ 2.92-3.16 (m, 4 H), 3.76 (t, J = 5.3 Hz, 1 H), 4.06 (br. s., 2 H), 4.39 (br. s., 1 H), 4.49- 4.93 (m, 5 H), 7.23 (d, J = 3.2 Hz, 1 H), 7.30-7.38 (m, 2 H), 7.44-7.54 (m, 2 H), 7.60 (d, J = 3.2 Hz, 1 H), 7.89 (d, J = 3.2 Hz, 1 H), 7.97 (d, J = 3.2 Hz, 1 H), 8.63 (s, 1 H), 9.12 (s, 1 H) MS m/z (M + H⁺) 491.2 1056 1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- pyrrolo[2,3-b]pyridine ¹H NMR (400 MHz, CDCl₃): δ 3.75 (s, 1 H), 4.11 (br. s., 2 H), 4.32-5.02 (m, 10 H), 6.75 (d, J = 3.6 Hz, 1 H), 7.23 (d, J = 8.9 Hz, 2 H), 7.53 (d, J = 3.7 Hz, 1 H), 7.61 (d, J = 3.2 Hz, 1 H), 7.65 (m, J = 9.0, 4.7 Hz, 2 H), 7.89 (d, J = 3.2 Hz, 1 H), 8.33 (d, J = 2.0 Hz, 1 H), 8.60 (d, J = 1.7 Hz, 1 H) MS m/z (M + H⁺) 491.2 1153 1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- pyrrolo[3,2-b]pyridine ¹H NMR (400 MHz, CDCl₃): δ 3.83-4.34 (m, 9 H), 4.41- 4.70 (m, 2 H), 5.14 (d, J = 5.8 Hz, 2 H), 6.90 (br. s., 1 H), 7.28 (d, J = 8.2 Hz, 2 H), 7.38-7.51 (m, 2 H), 7.62 (d, J = 3.2 Hz, 1 H), 7.65 (d, J = 2.9 Hz, 1 H), 7.85 (d, J = 8.6 Hz, 1 H), 7.90 (d, J = 3.2 Hz, 1 H), 7.99 (d, J = 8.6 Hz, 1 H) MS m/z (M + H⁺) 491.2 1306 1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4-(1,3-thiazol- 2-ylcarbonyl)-2-(trifluoromethyl)piperazine ¹H NMR (400 MHz, CD₃OD): δ 2.14 (dd, J = 22.7, 10.5 Hz, 1 H), 2.43 (dd, J = 41.6, 11. 7 Hz, 1 H), 2.87-3.18 (m, 1 H), 3.18-3.44 (m, 1.5 H), 3.58-3.81 (m, 0.5 H), 3.95- 4.17 (m, 1 H), 4.18-4.40 (m, 2 H), 4.49 (m, 1.5 H), 5.43 (d, J = 26.4 Hz, 1 H), 6.95 (br. s., 0.5 H), 7.33-7.43 (m, 1 H), 7.43-7.51 (m, 2 H), 7.66 (d, J = 7.6 Hz, 2 H), 7.70- 7.80 (m, 4 H), 7.88 (br. s., 1 H), 7.93-8.03 (m, 1 H) MS m/z (M + H⁺) 501.1 856 5-({3-[4-(1H-Pyrrol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 378 1116 2:1 mixture of 2 components: Major: 1-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-5- ({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1H-indole MS m/z (M + H⁺) 575.1 Minor: 1-[2-Fluoro-5-(trifluoromethyl)pyridin-3-yl]-5- ({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1H-indole MS m/z (M + H⁺) 559.0 1233 2-Phenyl-6-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3- yl]piperazin-1-yl}carbonyl)-1,3-benzoxazole MS m/z (M + H⁺)) 474.1

Example 9b

1-[1-[(6-Bromonaphthalen-2-yl)carbonyl]azetidin-3-yl]-4-(phenylcarbonyl)piperazine, Cpd 118

The title compound was prepared in an analogous manner to the preparation of Cpd 313 of Example 9, except commercially available N-benzoylpiperazine was used as starting material, instead of intermediate 9b. MS 478/480 (M+H⁺).

Following the procedure described above for Example 9b and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 119 7-Bromo-3-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)quinoline MS m/z (M + H⁺) 479/481 120 1-{1-[(5-Chloro-3-methyl-1-benzothiophen-2- yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine ¹H NMR (400 MHz, CD₃OD): δ 7.74 (d, J = 2 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.43-7.36 (m, 6H), 4.28 (m, 2H), 4.20-4.00 (m, 2H), 4.00-3.70 (m, 2H), 3.48 (m, 2H), 3.24 (m, 1H), 2.58 (s, 3H), 2.50-2.20 (m, 4H). MS m/z (M + H⁺) 454 121 2-Phenyl-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1,3-benzoxazole MS m/z (M + H⁺) 467 122 2-Methyl-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1,3-benzothiazole MS m/z (M + H⁺) 421 123 2-(4-Methoxyphenyl)-6-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole MS m/z (M + H⁺) 497 124 1-(Phenylcarbonyl)-4-(1-{[5-(trifluoromethyl)-1- benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 474 125 1-{1-[(6-Bromo-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}- 4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 484/486 126 5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole ¹H NMR (400 MHz, CD₃OD): δ 8.00 (s, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.6 Hz, 2H), 7.58 (s, 2H), 7.40 (m, 6H), 6.78 (d, J = 3.5 Hz, 1H), 4.37 (m, 1H), 4.30-4.20 (m, 2H), 4.11 (m, 1H), 3.60-3.40 (m, 2H), 3.24 (m, 1H), 2.50-2.20 (m, 4H). MS m/z (M + H⁺) 533 127 2-(4-Chlorophenyl)-6-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 500 128 1-Phenyl-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1H-indole ¹H NMR (400 MHz, CD₃OD): δ 7.98 (s, 1H), 7.56-7.37 (m, 13H), 6.73 (d, J = 3.2 Hz, 1H), 4.37 (m, 1H), 4.29-4.20 (m, 2H), 4.10 (bs, 1H), 3.90 (bs, 1H), 3.74 (bs, 1H), 3.38 (m, 2H), 3.23 (m, 1H), 2.50-2.20 (m, 4H). MS m/z (M + H⁺) 465 129 1-[3-(Trifluoromethyl)phenyl]-5-({3-[4- (phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole ¹H NMR (400 MHz, CD₃OD): δ 8.00 (s, 1H), 7.76 (s, 1H), 7.72-7.64 (m, 3H), 7.58-7.50 (m, 2H), 7.41 (m, 6 H), 6.78 (d, J = 3 Hz, 1H), 4.37 (m, 1H), 4.30-4.20 (m, 2H), 4.11 (m, 1H), 3.91 (bs, 1H), 3.75 (bs, 1H), 3.48 (m, 2H), 3.25 (m, 1H), 2.55-2.20 (m, 4H). MS m/z (M + H⁺) 533 130 5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1-(phenylsulfonyl)-1H-indole MS m/z (M + H⁺) 529 131 6-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-2-[3-(trifluoromethyl)phenyl]-1,3-benzoxazole ¹H NMR (400 MHz, CD₃OD): δ 8.54 (s, 1H), 8.45 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 1.2 Hz, 1H), 7.82 (m, 2H), 7.69 (m, 2H), 7.41 (m, 5H), 4.38 (m, 1H), 4.32-4.22 (m, 2H), 4.12 (m, 1H), 3.90 (bs, 1H), 3.76 (bs, 1H), 3.50 (bs, 2H), 3.27 (m, 1H), 2.50-2.20 (m, 4H). MS m/z (M + H⁺) 535 132 2-Phenyl-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1,3-benzoxazole MS m/z (M + H⁺) 467 617 1-(4-Fluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indazole MS m/z 484 (M + H⁺) 571 1-(3,4-Difluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indole ¹H NMR (CDCl₃, 400 MHz): δ 7.99 (s, 1 H), 7.53-7.63 (m, 1 H), 7.45-7.53 (m, 1 H), 7.16-7.45 (m, 9 H), 6.74 (d, J = 3.1 Hz, 1 H), 4.37 (br. s., 1 H), 4.16-4.32 (m, 2 H), 4.11 (br. s., 1 H), 3.83-4.00 (m, 1 H), 3.65-3.83 (m, 1 H), 3.48 (br. s., 2 H), 3.17-3.31 (m, 1 H), 2.44 (br. s., 4 H) MS m/z 501 (M + H⁺) 584 1-(4-Fluorophenyl)-3-methyl-5-({3-[4- (phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z 497 (M + H⁺) 599 2-(3-Fluorophenyl)-6-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,3-benzothiazole MS m/z 501 (M + H⁺) 583 1-(3-Fluorophenyl)-3-methyl-5-({3-[4- (phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z 497 (M + H⁺) 577 3-Methyl-1-phenyl-5-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z 479 (M + H⁺) 569 5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1-(3,4,5-trifluorophenyl)-1H-indole MS m/z 519 (M + H⁺) 573 5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1-[4-(trifluoromethoxy)phenyl]-1H-indole MS m/z 549 (M + H⁺) 580 1-(3,5-Difluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z 501 (M + H⁺) 568 1-(4-Chloro-3-fluorophenyl)-5-({3-[4- (phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z 517 (M + H⁺) 578 1-(2,5-Difluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z 501 (M + H⁺) 590 1-(3,4-Difluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indazole MS m/z 502 (M + H⁺)

Example 9c

Following the procedure described above for Example 1b, with the exception of using 1,10-phenanthroline instead of trans-N,N′-dimethylcyclohexane-1,2-diamine as a ligand in step K, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compound:

Following the procedure described above for Example 9, step D, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1375 2-Methyl-4-[5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)- 1H-indol-1-yl]benzonitrile MS m/z (M + H⁺) 511 1421 2-Methyl-4-[5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)- 1H-indol-1-yl]benzonitrile MS m/z (M + H⁺) 511 566 2-Methyl-4-[5-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indol-1- yl]benzonitrile MS m/z (M + H⁺) 504

Example 9d

E. Methyl 1-(4-cyanophenyl)-indole-5-carboxylate, 9d

was prepared according to Example 1a step H.

F. 1-(4-cyanophenyl)-indole-5-carboxylic acid, 9e and 1-(4-carbamoyl-phenyl)-indole-5-carboxylic acid, 9f

A mixture of methyl 1-(4-cyanophenyl)-indole-5-carboxylate, 9d (156 mg, 0.57 mmol) and LiOH (54 mg, 2.26 mmol) in THF (4 mL) and H₂O (2 mL) was stirred at room temperature for 4 days. Aqueous 10% HCl solution was added to the reaction mixture to adjust pH=3˜4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na₂SO₄ and concentrated. Purification by flash column chromatography (silica gel, 4-8% MeOH/CH₂Cl₂) gave 9e (75 mg), followed by 9f (27 mg).

Following the procedure described above for Example 9d and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Following the procedure described above for Example 9, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1159 4-[5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile MS m/z (M + H⁺) 497 1171 4-[5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzamide MS m/z (M + H⁺) 515 1133 4-[5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile MS m/z (M + H⁺) 497 1109 2-[5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile MS m/z (M + H⁺) 497 1182 2-[5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile MS m/z (M + H⁺) 497 1113 3-[5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile MS m/z (M + H⁺) 497 1177 3-[5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzamide MS m/z (M + H⁺) 515

Following the procedure described above for Example 9b, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 582 4-[5-({3-[4-(Phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indol-1- yl]benzonitrile MS m/z (M + H⁺) 490 588 2-[5-({3-[4-(Phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indol-1- yl]benzonitrile MS m/z (M + H⁺) 490 594 3-[5-({3-[4-(Phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzamide MS m/z (M + H⁺) 508

Example 9e

G. Ethyl 1-(3-trifluoromethyl-phenyl)-1H-indazole-5-carboxylate, 91 and Ethyl 1-(3-trifluoromethyl-phenyl)-1H-indazole-5-carboxylate, 9j

A mixture of ethyl 1H-Indazole-5-carboxylate 9g (150 mg, 0.79 mmol), 1-bromo-3-trifluoromethylbenzene 9h (0.13 mL, 0.95 mmol), CuI (22.5 mg, 0.12 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.056 mL, 0.36 mmol), and K₃PO₄ (0.37 g, 1.74 mmol) in toluene (1.5 mL) was heated at 110° C. for 16 hours. The reaction mixture was diluted with CH₂Cl₂ and filtered. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 10% EtOAc/heptane) to give 91 (190 mg), followed by 9j (37 mg).

H. 1-(3-Trifluoromethyl-phenyl)-1H-indazole-5-carboxylic acid, 9k and 1-(3-Trifluoromethyl-phenyl)-1H-indazole-5-carboxylic acid, 9l. 9k and 9l

were prepared according to Example 1b Step L from 9l and 9j respectively.

Following the procedure described above for Example 9e, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Following the procedure described above for Example 9, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1080 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]- 1H-indazole MS m/z (M + H⁺) 541 1374 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1-[3- (trifluoromethoxy)phenyl]-1H-indazole MS m/z (M + H⁺) 557 1376 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-2-[3- (trifluoromethoxy)phenyl]-2H-indazole MS m/z (M + H⁺) 557 1419 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1-[3-(trifluoromethyl)phenyl]- 1H-indazole MS m/z (M + H⁺) 541 1420 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-2-[3-(trifluoromethyl)phenyl]- 2H-indazole MS m/z (M + H⁺) 541 1422 5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-2-[3- (trifluoromethoxy)phenyl]-2H-indazole MS m/z (M + H⁺) 557

Following the procedure described above for Example 9b, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 575 5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H- indazole MS m/z (M + H⁺) 534 576 5-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1-[3-(trifluoromethoxy)phenyl]-1H- indazole MS m/z (M + H⁺) 550

Example 9f

I. Methyl 1-(4-cyano-3-fluorophenyl)-indole-5-carboxylate, 9m

was prepared according to Example 9e step H.

J. Methyl 1-(4-cyano-3-methoxyphenyl)-indole-5-carboxylate, 9n

A solution of 95 mg (0.32 mmol) of compound 9m was combined with 120 mg (0.87 mmol) of K₂CO₃ in 8 mL of MeOH and heated at 75° C. for 5 h. The mixture was cooled, diluted with water, and extracted with CH₂Cl₂. The organic solution was concentrated to give 100 mg (100%) of 9n as a white solid.

K. 1-(4-cyano-3-methoxyphenyl)-indole-5-carboxylic acid, 93 and 1-(4-carbamoyl-phenyl)-indole-5-carboxylic acid, 9o

A mixture of 100 mg (0.33 mmol) of compound 9m and LiOH (31 mg, 1.3 mmol) in THF (4 mL) and H₂O (2 mL) was stirred at room temperature for 3 days. Aqueous 10% HCl solution was added to the reaction mixture to adjust pH=3˜4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na₂SO₄ and concentrated to give 90 mg (94%) of compound 90 as a white solid.

Following the procedure described above for Example 9, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1115 2-Methoxy-4-[5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indol-1-yl]benzonitrile MS m/z (M + H⁺) 527 633 2-Methoxy-4-[5-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile MS m/z (M + H⁺) 520

Example 9g

L. Ethyl 2-(thiazol-2-yl)benzo[d]thiazole-6-carboxylate, 9q

A mixture of ethyl 2-bromo-benzothiazole-6-carboxylate 1w (150 mg, 0.53 mmol), 2-tributylstannylthiazole 9p (0.25 mL, 0.79 mmol), and Pd(PPh₃)₄ (30 mg, 0.03 mmol) in dioxane (2 mL) was heated at 130° C. for 30 min under microwave. The reaction mixture was diluted with CH₂Cl₂, washed with aq. NaHCO₃, dried over Na₂SO₄, and concentrated. Purification by flash column chromatography (silica gel, 10% EtOAc/heptane) gave 9q (130 mg).

M. 2-(Thiazol-2-yl)benzo[d]thiazole-6-carboxylic acid, 9r

Ethyl 2-phenyl-benzothiazole-6-carboxylate 9q (130 mg, 0.45 mmol) was stirred with LiOH (43 mg, 1.8 mmol) in THF (4 mL) and H₂O (2 mL) for 6 h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3˜4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na₂SO₄ and concentrated to give 9r (110 mg).

Following the procedure described above for Example 9g and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Following the procedure described above for Example 9, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1210 2-(1,3-Thiazol-2-yl)-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzothiazole MS m/z (M + H⁺) 497 1165 2-Pyridin-2-yl-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzothiazole MS m/z (M + H⁺) 491

Example 9h

N. Methyl 2-(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylate, 9u

A mixture of methyl 1,2,3,4-tetrahydroisoquinoline-8-carboxylate 9s (100 mg, 0.44 mmol), 2-bromopyrimidine 9t (77 nm, 0.48 mmol), and Et₃N (0.13 mL, 0.92 mmol) in acetonitrile (5 mL) was stirred at room temperature overnight. The reaction mixture was worked up to give crude 9v (187 mg).

M. 2-(Pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid, 9v

Compound 9u (187 mg, 0.44 mmol) was refluxed with 3N aqueous NaOH (0.25 mL mg, 0.75 mmol) in THF (6 mL) overnight. Concentrated HCl solution was added to the mixture to adjust pH to 3˜4. The resulting mixture was concentrated to give 9v (350 mg) as the tris-HCl salt.

Following the procedure described above for Example 9, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compound of the present invention was prepared:

Cpd Cpd Name and Data 2-Pyrimidin-2-yl-8-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4- tetrahydroisoquinoline MS m/z (M + H⁺) 490.1

Example 9i

N. Methyl 3-Amino-2-benzoylamino-benzoate, 9y

To a solution of 500 mg (3.0 mmol) of methyl 2,3-diaminobenzoate 9w and 730 mg (6.0 mmol) of benzoic acid 9x in 8 mL of CH₂Cl₂ was added 620 mg (3.0 mmol) of dicyclohexylcarbodiimide (DCC) and 4 mg (0.033 mmol) of DMAP. The reaction was stirred overnight and the solid was filtered off. The solid was purified by flash column chromoatography (silica gel, 10-30% gradient of EtOAc in heptanes) to give 220 mg (27%) of methyl 3-Amino-2-benzoylamino-benzoate, 9y. MS m/z (M+H⁺) 271.2

O. Methyl 2-phenyl-1H-benzo[d]imidazole-7-carboxylate, 9z

A solution of 810 mg (3.0 mmol) of methyl 3-amino-2-benzoylamino-benzoate 9y in 15 ml acetic acid was heated to 125° C. for 1.5 h. The reaction was cooled and poured into ice/water. The aqueous layer was made basic with NaHCO₃ and extracted with CH₂Cl₂. The organic solution was dried over Na₂SO₄ and evaporated to give 540 mg (71%) of methyl 2-phenyl-1H-benzo[d]imidazole-7-carboxylate, 9z. MS m/z (M+H⁺) 253.2

P. Phenyl-1H-benzo[d]imidazole-7-carboxylic acid, 9aa

A mixture of 540 mg (2.1 mmol) of methyl 2-phenyl-1H-benzo[d]imidazole-7-carboxylate 9z and 3 mL (9 mmol) of 3N aqueous NaOH was refluxed in 8 mL of THF overnight. After cooling, the mixture was poured into ice water and acidified with conc. HCl. The resulting solid was filtered and dried to give 440 mg (86%) of phenyl-1H-benzo[d]imidazole-7-carboxylic acid, 9aa. MS m/z (M+H⁺) 238.9.

Following the procedure described above for Example 9i, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Following the procedure described above for Example 9, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 608 2-(2-Chlorophenyl)-4-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 500.3 609 2-(3-Fluorophenyl)-4-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 484.3 602 2-(4-Fluorophenyl)-4-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 484.3 607 2-(4-Chlorophenyl)-4-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 500.3 601 2-Phenyl-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 466.3 1389 2-(3-Chlorophenyl)-7-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 507.2 1399 2-Furan-2-yl-7-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 463.2 1390 2-Phenyl-7-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 473.2 1387 2-Pyridin-4-yl-7-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 474.3 1252 2-Furan-2-yl-7-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 463.3 1255 2-Phenyl-7-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 463.3 1388 2-(2-Fluorophenyl)-4-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 491.2 1391 2-(3-Fluorophenyl)-4-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 491.2 1393 2-(4-Fluorophenyl)-4-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 491.2 1394 2-(2-Chlorophenyl)-4-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 507.2 1290 2-(4-Chlorophenyl)-4-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 507.2 980 2-Benzyl-4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 487 989 2-(2-Fluorobenzyl)-7-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 505.2 990 2-(3-Fluorobenzyl)-7-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 505.2 991 2-(4-Chlorobenzyl)-7-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 521.2 1461 2-(Pyridin-4-ylmethyl)-7-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 488.2

Example 9j

Q. Methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate, 9dd

A solution of 1.0 g (4.9 mmol) of methyl 2-amino-3-hydroxybenzoate 9bb, 1.03 g (7.4 mmol) of 4-fluorobenzoic acid 9 cc, 10 mL DMF and 2.9 mL (20.6 mmol) of TEA were placed into a flask and stirred for 10 min HATU (7.4 mmol, 2.8 g) was added and the reaction was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organics were washed with water and brine and the solvent was evaporated to give 1.2 g of crude product, methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate, 9dd, which was used without purification. MS m/z (M+H⁺) 290.1.

R. Methyl 2-(4-fluorophenyl)benzo[d]oxazole-4-carboxylate, 9ee

Methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate 9dd (7.4 mmol, 1.2 g crude) and 1.3 g (7.5 mmol) of p-toluenesulfonic acid was refluxed in 10 mL of xylene overnight. After cooling saturated NaHCO₃ was added and the resulting mixture was extracted with EtOAc. The organic solvent was evaporated to give 1.1 g (55%) of methyl 2-(4-fluorophenyl)benzo[d]oxazole-4-carboxylate, 9ee. MS m/z (M+H⁺) 272.0.

S. 2-(4-Fluorophenyl)-benzo[d]oxazole-4-carboxylic acid, 9ff

A mixture of 1.1 g (4.0 mmol) methyl 2-(4-fluorophenyl)benzo[d]oxazole-4-carboxylate 9ee and 3.7 mL of 3N aqueous NaOH in 10 mL of THF was refluxed overnight. After cooling the reaction mixture was poured into water and acidified with conc. HCl. The resulting solid was filtered and dried to give 830 mg (79%) of 2-(4-fluorophenyl)-benzo[d]oxazole-4-carboxylic acid, 9ff. MS m/z (M+H⁺) 258.1.

Following the procedure described above for Example 9j, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Following the procedure described above for Example 9, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1154 2-Phenyl-7-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole ¹H NMR (400 MHz, CDCl₃): δ 8.32 (m, 2H); 7.95 (m, 2H); 7.85 (m, 1H); 7.71-7.49 (m, 5H); 4.85-4.44 (bm, 3H); 4.15-3.91 (bm, 3H); 3.23 (bm, 3H) MS m/z (M + H⁺) 474.2 1254 2-(3-Fluorophenyl)-7-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzoxazole MS m/z (M + H⁺) 492.1 1282 2-(4-Fluorophenyl)-7-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzoxazole MS m/z (M + H⁺) 492.1 1238 2-(3-Chlorophenyl)-7-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzoxazole MS m/z (M + H⁺) 507.9 1380 2-(4-Chlorophenyl)-7-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzoxazole ¹H NMR (400 MHz, CDCl₃): δ 9.05 (bs, 1H); 8.3 (d, 2H); 8.2 (m, 1H); 7.95 (d, 1H); 7.66 (t, 3H); 7.44 (t, 1H); 4.69-4.52 (m, 1H); 4.44 (m, 2H); 4.10 (bm, 2H); 3.20 (m, 4H). MS m/z (M + H⁺) 507.9 1190 2-Phenyl-4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole MS m/z (M + H⁺) 474 1193 2-(2-Fluorophenyl)-4-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzoxazole MS m/z (M + H⁺) 492.2 1257 2-(4-Fluorophenyl)-4-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzoxazole MS m/z (M + H⁺) 492.2 1173 2-(2-Chlorophenyl)-4-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzoxazole MS m/z (M + H⁺) 508.2 1191 2-(3-Chlorophenyl)-4-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzoxazole MS m/z (M + H⁺) 508.2 1220 2-(4-Chlorophenyl)-4-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzoxazole MS m/z (M + H⁺) 508.9 1237 2-Phenyl-7-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole MS m/z (M + H⁺) 474.2 1251 2-Pyridin-3-yl-4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole MS m/z (M + H⁺) 475.1

Example 10

A. 6-Trifluoromethyl-benzo[b]thiophene-2-carbonyl chloride, 10b

To compound 10a (0.13 g, 0.53 mmol) in CH₂Cl₂ (5 mL) at room temperature was added (COCl)₂ (0.051 mL, 0.58 mmol), followed by 2 drops of DMF. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated to give compound 10b, which was used in the next reaction without further purification.

B. 1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine

To a solution of compound 5e (60 mg, 0.24 mmol) and Et₃N (0.08 mL, 0.58 mmol) in CH₂Cl₂ (3 mL) at 0° C. was added a solution of compound 10b (0.53 mmol) in CH₂Cl₂ (1 mL). The reaction was slowly warmed up to room temperature over 4.5 h, diluted with CH₂Cl₂, and washed with aq. NaHCO₃. The organic layer was dried over Na₂SO₄ and concentrated. Purification by flash column chromatography (silica gel, 3% MeOH/CH₂Cl₂) afforded compound 323. ¹H NMR (400 MHz, CD₃OD): δ 8.15 (s, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.89 (d, J=3 Hz, 1H), 7.74 (s, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.56 (d, J=3 Hz, 1H), 4.60 (m, 2H), 4.45 (m, 2H), 4.30 (m, 1H), 4.16 (m, 1H), 3.95-3.89 (m, 2H), 3.35 (m, 1H), 2.55 (bs, 4H). MS m/z (M+H⁺) 481.

Following the procedure described above for Example 10 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 324 1-(1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹H NMR (400 MHz, CD₃OD): δ 8.13 (s, 1H), 8.01 (d, J = 8 Hz, 1H), 7.88 (d, J = 3 Hz, 1H), 7.73 (d, J = 8 Hz, 1H), 7.55 (d, J = 3 Hz, 1H), 4.53 (bs, 1H), 4.46 (bs, 1H), 4.31 (m, 2H), 4.22 (m, 1H), 4.16 (m, 1H), 3.33 (m, 1H), 2.60-2.40 (m, 4H). MS m/z (M + H⁺) 515 325 1-(Phenylcarbonyl)-4-(1-{[6-(trifluoromethyl)-1- benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (400 MHz, CD₃OD): δ 8.15 (s, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.73 (s, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.42 (m, 5H), 4.58 (m, 1H), 4.42 (m, 1H), 4.28 (m, 1H), 4.12 (m, 1H), 3.93 (bs, 1H), 3.77 (bs, 1H), 3.51 (bs, 2H), 3.34 (m, 1H), 2.60-2.30 (m, 4H). MS m/z (M + H⁺) 474 686 3-Methyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)thieno[2,3- b]pyridine MS m/z (M + H⁺) 496 749 3-Methyl-2-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-6-(trifluoromethyl)thieno[2,3- b]pyridine MS m/z (M + H⁺) 496 801 1-(1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-ylcarbonyl)-2- (trifluoromethyl)piperazine MS m/z (M + H⁺) 583.0 833 4-(1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-1-(1,3-thiazol-4-ylcarbonyl)-2- (trifluoromethyl)piperazine MS m/z (M + H⁺) 583.0 778 1-(1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)-2- (trifluoromethyl)piperazine ¹H NMR (400 MHz, CD₃OD): δ 2.13 (d, J = 13.2 Hz, 1 H), 2.41 (d, J = 47.2 Hz, 1 H), 2.8-3.3 (m, 2.5 H), 3.69 (d, J = 13.7 Hz, 0.5 H), 3.98-4.42 (m, 4 H), 4.51 (t, J = 13.4 Hz, 0.5 H), 5.27-5.54 (m, 1 H), 6.93 (br. s., 0.5 H), 7.83 (d, J = 8.6 Hz, 1 H), 7.88 (br. s., 1 H), 7.97 (t, J = 6.8 Hz, 1 H), 8.11 (d, J = 8.8 Hz, 1 H), 8.42 (s, 1 H) MS m/z (M + H⁺) 583.0

Example 10a

C. Methyl 3-chloro-5-fluoro-6-trifluoromethyl-benzo[b]thiophene-2-carboxylate, 10d and methyl 3-chloro-6-trifluoromethyl-7-fluoro-benzo[b]thiophene-2-carboxylate, 10e

A mixture of 3-fluoro-4-(trifluoromethyl)-cinnamic acid 10c (1.5 g, 6.4 mmol), SOCl₂ (2.33 mL, 32 mmol), DMF (0.05 mL, 0.64 mmol), and pyridine (0.05 mL, 0.64 mmol) in chlorobenzene (5 mL) was heated to reflux for 24 h. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was dissolved in MeOH (50 mL) and stirred at room temperature for 16 h. The solution was concentrated, diluted with CH₂Cl₂ and washed with H₂O. The organic solution was dried over Na₂SO₄ and concentrated. Recrystallization with heptanes, followed by flash column chromatography (silica gel, 2% EtOAc/heptane) gave 10d (580 mg) and 10e (380 mg).

D. 3-Chloro-5-fluoro-6-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid, 10f

Methyl 3-chloro-5-fluoro-6-trifluoromethyl-benzo[b]thiophene-2-carboxylate 10d (180 mg, 0.58 mmol) was stirred with LiOH (55 mg, 2.3 mmol) in THF (5 mL) and H₂O (2.5 mL) for 4 h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3˜4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na₂SO₄ and concentrated to give 10f (150 mg).

E. 3-Chloro-6-trifluoromethyl-7-fluoro-benzo[b]thiophene-2-carboxylic acid, 10g

Compound 10g was prepared from 10e following the procedure described in above step D.

Following the procedure described above for Example 10, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 666 1-(1-{[3-Chloro-5-fluoro-6-(trifluoromethyl)-1- benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3- thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 533 900 1-(1-{[3-Chloro-5-fluoro-6-(trifluoromethyl)-1- benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 533 670 1-(1-{[3-Chloro-7-fluoro-6-(trifluoromethyl)-1- benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3- thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 533 650 1-(1-{[3-Chloro-7-fluoro-6-(trifluoromethyl)-1- benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 533

Example 10b

F. 3-Chloro-5-trifluoromethyl-6-fluoro-benzo[b]thiophene-2-carboxylic acid, 10h and 3-chloro-6-fluoro-7-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid, 10i

Compounds 10h and 10i were prepared according to Example 10a, using 4-fluoro-3-(trifluoromethyl)-cinnamic acid in place of 10c, and were obtained as a ˜2:1 mixture.

G. 3-Chloro-5-trifluoromethyl-6-fluoro-benzo[b]thiophene-2-carbonyl chloride, 10j and 3-chloro-6-fluoro-7-trifluoromethyl-benzo[b]thiophene-2-carbonyl chloride, 10k

Compounds 10j and 10k were prepared according to Example 10a from 10h and 10i, and were obtained as a ˜2:1 mixture.

H. 1-(1-{[3-Chloro-6-fluoro-5-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 901, and 1-(1-{[3-chloro-6-fluoro-7-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 902

Cpd 901 and Cpd 902 were prepared according to Example 10 from 5e bis HCl salt (0.31 mmol, 150 mg), the mixture of 10j and 10k (0.24 mmol, 76 mg), and Et₃N (1.44 mol, 0.2 mL) in 7 mL of CH₂Cl₂. Workup and purification by flash column chromatography (silica gel, 2% MeOH/CH₂Cl₂) gave 50 mg (39%) of Cpd 901 followed by 18 mg (14%) of Cpd 902. Cpd 901: MS m/z (M+H⁺) 533. Cpd 902: MS m/z (M+H⁺) 533.

Following the procedure described above for Example 10b, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 659 1-(1-{[3-Chloro-6-fluoro-5-(trifluoromethyl)-1- benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol- 4-ylcarbonyl)piperazine MS m/z (M + H⁺) 533 697 1-(1-{[3-Chloro-6-fluoro-7-(trifluoromethyl)-1- benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol- 4-ylcarbonyl)piperazine MS m/z (M + H⁺) 533

Example 11

A. 1-{4-[1-(6-Bromo-3-chloro-benzo[b]thiophene-2-carbonyl)-azetidin-3-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone, 11b

To a solution of compound 1 g (0.19 g, 0.61 mmol) and Et₃N (0.51 mL, 3.67 mmol) in CH₂Cl₂ (4 mL) at 0° C. was added a solution of compound 11a (prepared in an analogous manner to that of compound 10b of Example 10) (0.69 mmol) in CH₂Cl₂ (2 mL). The reaction mixture was slowly warmed up to room temperature over 18 h. The reaction mixture was diluted with CH₂Cl₂ and washed with aq. NaHCO₃. The organic layer was dried over Na₂SO₄ and concentrated. Purification by flash column chromatography (silica gel, 3% MeOH/CH₂Cl₂) gave compound 11b (0.3 g).

B. (6-Bromo-3-chloro-benzo[b]thiophen-2-yl)-(3-piperazin-1-yl-azetidin-1-yl)-methanone, 11c

A solution of compound 11b (0.3 g, 0.59 mmol) in Et₃N (1 mL) and MeOH (9 mL) was stirred at room temperature for 3 days. It was then concentrated to give compound 11c, which was used in the next reaction without further purification.

C. 1-{1-[(6-Bromo-3-chloro-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 326

To a mixture of compound 11c (0.2 mmol), compound 5c (31 mg, 0.24 mmol), and Et₃N (0.08 mL, 0.58 mmol) in CH₂Cl₂ (3 mL) at room temperature was added HATU (91 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 18 h. It was diluted with diethyl ether, washed with aq. NaHCO₃ and aq. NaCl, dried over Na₂SO₄, filtered, and concentrated. Purification by flash column chromatography (silica gel, 3% MeOH/CH₂Cl₂) gave compound 326 (57 mg). ¹H NMR (400 MHz, CD₃OD): δ 7.98 (s, 1H), 7.88 (d, J=3 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 7.55 (d, J=3 Hz, 1H), 4.53 (bs, 1H), 4.44 (bs, 1H), 4.30 (bs, 2H), 4.21 (bs, 1H), 4.13 (bs, 1H), 3.89 (bs, 1H), 3.84 (bs, 1H), 3.31 (m, 1H), 2.60-2.40 (m, 4H). MS m/z (M+H⁺) 525/527/529.

Following the procedure described above for Example 11 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 327 1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[4-(trifluoromethyl)-1- benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (400 MHz, CD₃OD): δ 8.05 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 3 Hz, 1H), 7.85 (s, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.55 (d, J = 3 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 4.60 (m, 2H), 4.45 (m, 2H), 4.31 (m, 1H), 4.17 (m, 1H), 3.95-3.80 (m, 2H), 3.35 (m, 1H), 2.56 (bs, 4H). MS m/z (M + H⁺) 481 328 1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[7-(trifluoromethyl)-1- benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 481 329 1-(Phenylcarbonyl)-4-(1-{[7-(trifluoromethyl)-1- benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (400 MHz, CD₃OD): δ 8.02 (d, J = 8.2 Hz, 1H), 7.80 (s, 1H), 7.73 (d, J = 7.4 Hz, 1H), 7.51 (t, J = 8.2 Hz, 1H), 7.42 (m, 5H), 4.60 (m, 1H), 4.43 (m, 1H), 4.28 (m, 1H), 4.12 (m, 1H), 3.94 (bs, 1H), 3.76 (bs, 1H), 3.51 (bs, 2H), 3.33 (m, 1H), 2.60-2.30 (m, 4H). MS m/z (M + H⁺) 474 330 1-(Phenylcarbonyl)-4-(1-{[4-(trifluoromethyl)-1- benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (400 MHz, CD₃OD): δ 8.05 (d, J = 8 Hz, 1H), 7.84 (s, 1S), 7.71 (d, J = 8 Hz, 1H), 7.50 (t, J = 8 Hz, 1H), 7.42 (m, 5H), 4.59 (m, 1H), 4.42 (m, 1H), 4.29 (m, 1H), 4.13 (m, 1H), 3.92 (bs, 1H), 3.79 (bs, 1H), 3.51 (bs, 1H), 3.34 (m, 1H), 2.60- 2.30 (m, 4H). MS m/z (M + H⁺) 474 331 1-{1-[(6-Bromo-3-chloro-1-benzothiophen-2- yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 518/520/522 332 1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[7-(trifluoromethyl)-1- benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (400 MHz, CD₃OD): δ 8.80 (s, 1H), 8.04 (s, 1H), 8.02 (d, J = 8 Hz, 1H), 7.81 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 4.60 (m, 1H), 4.45 (m, 1H), 4.30 (m, 1H), 4.15 (m, 1H), 4.02 (bs, 1H), 3.95 (m, 2H), 3.82 (bs, 1H), 3.35 (m, 1H), 2.60-2.40 (m, 4H). MS m/z (M + H⁺) 481 333 1-{1-[(6-Bromo-3-chloro-1-benzothiophen-2- yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹H NMR (400 MHz, CD₃OD): δ 8.80 (s, 1H), 8.02 (s, 1H), 7.97 (s, 1H), 7.74 (m, 1H), 7.60 (m, 1H), 4.30 (m, 2H), 4.21 (bs, 1H), 4.12 (bs, 1H), 4.00 (bs, 1H), 3.92 (m, 2H), 3.81 (bs, 1H), 3.31 (m, 1H), 2.50-2.30 (m, 4H). MS m/z (M + H⁺) 525/527/529 334 1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[4-(trifluoromethyl)-1- benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (400 MHz, CD₃OD): δ 8.80 (s, 1H), 8.05 (d, J = 8 Hz, 1H), 8.04 (s, 1H), 7.85 (m, 1H), 7.72 (d, J = 8 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 4.60 (m, 1H), 4.44 (m, 1H), 4.30 (m, 1H), 4.16 (m, 1H), 4.10-3.80 (m, 4H), 3.36 (m, 1H), 2.60-2.40 (m, 4H). MS m/z (M + H⁺) 481 335 1-(1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹H NMR (400 MHz, CD₃OD): δ 8.80 (d, J = 2 Hz, 1H), 8.13 (t, J = 0.8 Hz, 1H), 8.03 (d, J = 2 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.73 (dd, J = 1.2 Hz, 8.6 Hz, 1H), 4.31 (m, 2H), 4.21 (m, 1H), 4.15 (m, 1H), 4.01 (m, 1H), 3.93 (m, 2H), 3.81 (m, 1H), 3.33 (m, 1J), 2.55-2.40 (m, 4H). MS m/z (M + H⁺) 515 336 1-(1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 508 337 1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[6-(trifluoromethyl)-1- benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 481 504 1-(1-{[3-Methyl-5-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 488 543 1-{1-[(3-Chloro-6-fluoro-1-benzothiophen-2- yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 458 516 1-{1-[(6-Fluoro-3-methyl-1-benzothiophen-2- yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 438 908 1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[5-(trifluoromethyl)-1- benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 481 897 1-(1-{[3-Methyl-5-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 495 898 1-(1-{[3-Methyl-5-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 495 929 1-{1-[(3-Chloro-6-fluoro-1-benzothiophen-2- yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 465 930 1-{1-[(3-Chloro-6-fluoro-1-benzothiophen-2- yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 465 810 1-{1-[(3-Chloro-6-fluoro-1-benzothiophen-2- yl)carbonyl]azetidin-3-yl}-4-(pyridin-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 459 742 1-{1-[(6-Fluoro-3-methyl-1-benzothiophen-2- yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 445 684 1-{1-[(6-Fluoro-3-methyl-1-benzothiophen-2- yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 445

Example 12

1-{1-[(5-Phenylnaphthalen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 338

A mixture of compound 313 (48 mg, 0.1 mmol), compound 12a (24 mg, 0.2 mmol), K₂CO₃ (27 mg, 0.2 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (4 mg, 0.005 mmol) in EtOH (1 mL) and H₂O (0.2 mL) was heated in a microwave reactor at 130° C. for 30 min. The reaction mixture was cooled to room temperature, diluted with CH₂Cl₂, and washed with H₂O. The organic layer was dried over Na₂SO₄ and concentrated. Purification by flash column chromatography (silica gel, 3% MeOH/CH₂Cl₂) gave compound 338 (28 mg). ¹H NMR (400 MHz, CD₃OD): δ 8.20 (d, J=1.6 Hz, 1H), 7.93 (t, J=9.6 Hz, 2H), 7.88 (d, J=3 Hz, 1H), 7.66-7.43 (m, 9H), 4.52 (bs, 1H), 4.50-4.20 (m, 4H), 4.16 (m, 1H), 3.88 (bs, 1H), 3.83 (bs, 1H), 3.28 (m, 1H), 2.60-2.40 (m, 4H). MS m/z (M+H⁺) 483.

Following the procedure described above for Example 12 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 339 1-(Phenylcarbonyl)-4-{1-[(6-phenylnaphthalen-2- yl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 476 340 7-Phenyl-3-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)quinoline MS m/z (M + H⁺) 477 341 1-(Phenylcarbonyl)-4-[1-({6-[4-(trifluoromethyl)phenyl]-1- benzothiophen-2-yl}carbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 550 342 1-{1-[(6-Phenyl-1-benzothiophen-2-yl)carbonyl]azetidin-3- yl}-4-(phenylcarbonyl)piperazine ¹H NMR (400 MHz, CD₃OD): δ 8.05 (s, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.70 (s, 1H), 7.66-7.62 (m, 3H), 7.49-7.36 (m, 8H), 4.58 (m, 1H), 4.42 (m, 1H), 4.28 (m, 1H), 4.11 (m, 1H), 3.92 (bs, 1H), 3.76 (bs, 1H), 3.49 (bs, 2H), 3.31 (m, 1H), 2.60-2.25 (m, 4H). MS m/z (M + H⁺) 482

Example 13

1-{1-[(3-Chloro-6-phenyl-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 343

The title compound was prepared in an analogous manner to that of compound 338 of Example 12, using 1 equivalent of compound 12a, and substituting compound 326 for compound 313. The reaction was heated in a microwave reactor at 120° C. for 20 min ¹H NMR (400 MHz, CD₃OD): δ 8.01 (d, J=1.2 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.88 (d, J=3 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.66 (d, J=8.2 Hz, 2H), 7.55 (d, J=3 Hz, 1H), 7.49 (m, 2H), 7.41 (m, 1H), 4.54 (bs, 1H), 4.46 (bs, 1H), 4.33 (m, 2H), 4.25 (m, 1H), 4.14 (m, 1H), 3.89 (bs, 1H), 3.84 (bs, 1H), 3.32 (m, 1H), 2.50 (m, 4H). MS m/z (M+H⁺) 523.

Following the procedure described above for Example 13 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 344 1-{1-[(3-Chloro-6-phenyl-1-benzothiophen-2- yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 516 (M + H⁺). 345 1-{1-[(3-Chloro-6-phenyl-1-benzothiophen-2- yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 523 591 1-(Phenylcarbonyl)-4-(1-{[3-phenyl-6-(trifluoromethyl)-1- benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 550 515 1-(1-{[3-Cyclopropyl-6-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 514 511 1-(1-{[3-(2-Methylprop-1-en-1-yl)-6-(trifluoromethyl)-1- benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 528

Example 14

1-(Phenylcarbonyl)-4-{1-[(5-phenylthiophen-2-yl)carbonyl]azetidin-3-yl}piperazine, Cpd 346

A mixture of compound 322 (40 mg), compound 12a (16 mg), Pd(dppf)Cl₂.CH₂Cl₂ (8 mg), and Na₂CO₃ (19 mg), in a dioxane (0.8 mL)/water (0.2 mL) mixture, was placed in a capped vial and heated at 80° C. for 4 h. The reaction mixture was then diluted with EtOAc and water. The organic layer was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 5% MeOH/EtOAc) to give compound 346 (17 mg). MS m/z (M+H⁺) 432.6.

Following the procedure described above for Example 14 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 347 1-(Phenylcarbonyl)-4-[1-({5-[4- (trifluoromethyl)phenyl]thiophen-2-yl}carbonyl)azetidin-3- yl]piperazine MS m/z (M + H⁺) 500.0 924 1-Acetyl-6-phenyl-2-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4- tetrahydroquinoline MS m/z (M + H⁺) 530.0 917 1-Acetyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-6-[3-(trifluoromethyl)phenyl]- 1,2,3,4-tetrahydroquinoline MS m/z (M + H⁺) 598.0 919 1-Acetyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-6-[4-(trifluoromethyl)phenyl]- 1,2,3,4-tetrahydroquinoline MS m/z (M + H⁺) 598.0 920 1-Acetyl-6-(5-chlorothiophen-2-yl)-2-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4- tetrahydroquinoline MS m/z (M + H⁺) 570.1 1157 1-(1-{[4-(4-Fluorophenyl)thiophen-2-yl]carbonyl}azetidin-3- yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 457.0 1160 1-(1-{[4-(3-Fluorophenyl)thiophen-2-yl]carbonyl}azetidin-3- yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 457.0 1321 1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[3- (trifluoromethyl)phenyl]thiophen-2-yl}carbonyl)azetidin-3- yl]piperazine MS m/z (M + H⁺) 507.0 605 1-{1-[(5-Phenyl-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 466 600 7-(3-Fluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 483 1342 1-{1-[(5-Phenyl-1-benzofuran-2-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 473 1343 1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({5-[3- (trifluoromethyl)phenyl]-1-benzofuran-2-yl}carbonyl)azetidin- 3-yl]piperazine MS m/z (M + H⁺) 541 1059 1-(1-{[4-(3-Fluorophenyl)-5-methylthiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 471 1351 1-[1-({5-Methyl-4-[3-(trifluoromethyl)phenyl]thiophen-2- yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 521 1066 7-(3-Fluorophenyl)-1-methyl-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 504 1101 7-(4-Fluorophenyl)-1-methyl-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 504 1060 1-Methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-7-[3-(trifluoromethyl)phenyl]-1H- indole MS m/z (M + H⁺) 554 1352 1-[1-({4-Methyl-5-[4-(trifluoromethyl)phenyl]thiophen-2- yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 521 1353 1-(1-{[5-(4-Fluorophenyl)-4-methylthiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine 1065 1-(1-{[5-(3-Fluorophenyl)-4-methylthiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 471 1354 1-[1-({4-Methyl-5-[3-(trifluoromethyl)phenyl]thiophen-2- yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 521 1183 7-(3-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 490 1096 1-(1-{[4-(4-Fluorophenyl)-5-methylthiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 471

Example 14a

Following the procedure described above for Example 14, substituting Cpd 682 of Example 5 for Cpd 322 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1075 5-(4-Fluorophenyl)-3-methyl-2-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole ¹H NMR (400 MHz, CDCl₃): δ 7.93 (ar, 1H); 7.82 (ar, 1H); 7.76 (ar, 1H); 7.64 (m, 2H); 7.46 (m, 2H); 7.15 (m, 2H); 4.47-4.0 (bm, 6H); 3.82 (b, 2H); 2.5 (s, 3H) MS m/z (M + H⁺) 504.1 1149 5-(2-Fluoropyridin-3-yl)-3-methyl-2-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole ¹H NMR (400 MHz, CDCl₃): δ 8.09-7.97 9m, 2H); 7.88 (ar, 1H); 7.82-7.72 (m, 2H); 7.42 (ar, 2H); 7.31 (m, 1H); 7.62 (bm, 1H); 4.48 (bm, 1H); 4.35 (bm, 2H); 3.96 (bm, 2H); 3.14 (m, 4H); 2.44 (s, 3H) MS m/z (M + H⁺) 505.2 1175 5-(5-Methoxypyridin-3-yl)-3-methyl-2-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 517.2 1205 3-Methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-({3-[4-(1,3- thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)- 1H-indole MS m/z (M + H⁺) 490.2

Example 14b

Following the procedure described above for Example 14, substituting Cpd 792 of Example 5 for Cpd 322 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1204 6-(4-Fluorophenyl)-2-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 491.1 1241 6-(1-Methyl-1H-pyrazol-5-yl)-2-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 477.3 1244 6-(2-Fluoropyridin-3-yl)-2-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 491.2 1211 6-(3,5-Dimethylisoxazol-4-yl)-2-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 491.1 1196 6-(5-Methoxypyridin-3-yl)-2-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 503.1

Example 14c

Following the procedure described above for Example 14, substituting Cpd 864 of Example 5 for Cpd 322 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1213 5-(4-Fluorophenyl)-2-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)furo[2,3- b]pyridine MS m/z (M + H⁺) 492.1 1209 5-Phenyl-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)furo[2,3-b]pyridine MS m/z (M + H⁺) 474.1

Example 14d

Following the procedure described above for Example 14, substituting Cpd 315 of Example 5 for Cpd 322 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1443 5-Fluoro-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 415.2 1476 5-(2-Fluoropyridin-3-yl)-2-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 492.1 1303 2-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-5-[4-(trifluoromethoxy)phenyl]-1H- benzimidazole MS m/z (M + H⁺) 494.97 1294 5-(4-Fluorophenyl)-2-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole; MS m/z (M + H⁺) 491.1

Example 15

1-(Phenylcarbonyl)-4-(1-{[5-(phenylethynyl)thiophen-2-yl]carbonyl}azetidin-3-yl)piperazine, Cpd 348

To a solution of compound 322 (100 mg), compound 15a (0.46 mmol, 0.05 mL), CuI (4.4 mg), and Pd(PPh₃)₂Cl₂ (16 mg) in THF (1 mL) was added TEA (0.25 mL) and the mixture was heated at 40° C. for 1 h. The reaction was diluted with EtOAc and water. The organics were concentrated and purified by flash column chromatography (silica gel, 5% MeOH/EtOAc) to yield compound 348 (75 mg). MS m/z (M+H⁺) 456.6.

Example 16

1-(Phenylcarbonyl)-4-(1-{[5-(2-phenylethyl)thiophen-2-yl]carbonyl}azetidin-3-yl)piperazine, Cpd 349

To a solution of compound 348 (30 mg) in EtOH (20 mL) was added 10% Pd/C (10 mg) and the mixture was subjected to hydrogenation (45 psi H₂) for 1.5 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give compound 349 (30 mg). MS m/z (M+H⁺) 460.6.

Example 17

A. 6-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline, 17a

To a solution of compound 319 (500 mg) in CH₂Cl₂ (6 mL) was added TFA (4 mL) at room temperature. The mixture was stirred for 1.5 h and was then concentrated under reduced pressure. The residue was diluted with CH₂Cl₂ and made basic with aqueous 2N NaOH solution. The organic layer was washed with water and brine, dried over anhydrous K₂CO₃, filtered, and concentrated to give compound 17a, which was used without further purification.

B. 2-(Cyclohexylcarbonyl)-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline, Cpd 350

A mixture of compound 17a (31 mg, 0.03 mL), HATU (100 mg), and TEA (0.11 mL) in DCM (1 mL) was stirred at room temperature for 5 h. The reaction was diluted with DCM and water. The organics were concentrated and purified by flash column chromatography (silica gel, 8% MeOH/EtOAc) to give compound 350 (65 mg). ¹H NMR (CDCl₃): δ 7.47-7.39 (m, 7H), 7.17 (d, J=0.02, 1H), 4.74 (s, 1.2H), 4.48 (s, 0.8H), 4.25 (m, 2H), 4.10 (m, 2H), 3.92-3.71 (m, 4H), 3.43 (m, 2H), 3.19 (m, 1H), 2.93 (m, 1.2H), 2.86 (m, 0.8H), 2.55 (m, 1H), 2.42-2.24 (m, 4H), 1.83-1.57 (m, 8H), 1.26 (m, 2H). MS m/z (M+H⁺) 515.7.

Following the procedure described above for Example 17 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 351 2-(3,3-Dimethylbutanoyl)-6-({3-[4-(phenylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 503.7 352 2-(3,3-Dimethylbutanoyl)-6-({3-[4-(phenylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 509.6 353 2-[(4,4-Difluorocyclohexyl)carbonyl]-6-({3-[4- (phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)- 1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 463.6 354 6-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-2-{[4-(trifluoromethyl)cyclohexyl]carbonyl}- 1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 583.7 546 1-(1-{[4-(1-Acetylpiperidin-4-yl)phenyl]carbonyl}azetidin-3- yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 475.2 1486 1-[1-({2-[(3S)-1-Acetylpyrrolidin-3- yl]phenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 461.2 1437 2-(Phenylcarbonyl)-8-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4- tetrahydroisoquinoline MS m/z (M + H⁺) 516.2

Example 17a

D. 6-{3-[4-(Thiazole-2-carbonyl)-piperazin-1-yl]-azetidine-1-carbonyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, 17c

To a solution of compound 5e (651 mg, 2 mmol), 3,4-dihydro-1H-isoquinoline-2,6-dicarboxylic acid 2-tert-butyl ester 17b (555 mg, 2 mmol), and EDC (466 mg, 3 mmol) in CH₂Cl₂ (20 mL) was added Et₃N (0.84 mL, 6 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was extracted with CH₂Cl₂, and H₂O after acidifying the water layer to pH˜6 with 1N aqueous HCl. The organic solution was dried over Na₂SO₄ and concentrated. Purification of the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc) gave 17c (826 mg). MS m/z (M+H⁺) 512.1.

Following the procedure described above for Example 17a, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Following the procedure described above for Example 17a, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 538 tert-Butyl 4-[3-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)phenyl]piperidine-1-carboxylate MS m/z (M + H⁺) 533.4 903 tert-Butyl 4-[4-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)phenyl]piperidine-1- carboxylate MS m/z (M + H⁺) 540.1 861 tert-Butyl 8-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-3,4-dihydroisoquinoline- 2(1H)-carboxylate MS m/z (M + H⁺) 512.2

Example 17b

E. 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline, Cpd 916

To a solution of compound 17c (826 mg, 1.61 mmol) in CH₂Cl₂ (5 mL) was added trifluoroacetic acid (1 mL) at room temperature. The mixture was stirred at room temperature for 18 h. The mixture was extracted with CH₂Cl₂, and H₂O after basifying the water layer to pH˜8 with 1N aqueous NaOH. The organic solution was dried over Na₂SO₄ and concentrated. Purification of the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc) gave Cpd 916 (675 mg). ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J=3.3 Hz, 1H), 7.55 (d, J=3.3 Hz, 1H), 7.41 (s, 1H), 7.37 (d, J=8.03 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 4.54 (br. s., 1H), 4.44 (br. s., 1H), 4.01-4.35 (m, 6H), 3.75-3.95 (m, 2H), 3.12-3.31 (m, 2H), 2.85 (t, J=5.8 Hz, 1H), 2.49 (br. s., 4H). MS m/z (M+H⁺) 412.0.

Following the procedure described above for Example 17b, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Example 18

2-Benzyl-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline, Cpd 355

To a suspension of compound 17a (100 mg) and K₂CO₃ (69 mg) in MeCN was added compound 18a (0.0353 mL) and the mixture was stirred at room temperature for 30 min. The reaction was concentrated and the residue was diluted with EtOAc and water. The organics were concentrated and purified by flash column chromatography (silica gel, 8% MeOH/EtOAc) to afford compound 355 (85 mg). MS m/z (M+H⁺) 495.6.

Example 19

N-tert-Butyl-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide, Cpd 356

To a solution of compound 17a (75 mg) in DCM (1 mL) was dropwise added compound 19a (0.026 mL) at 0° C. After 30 min, the reaction mixture was quenched with DCM and water at 0° C. The organics were concentrated and purified by flash column chromatography (silica gel, 5% MeOH/EtOAc) to give compound 356 (60 mg). MS m/z (M+H⁺) 504.7.

Example 20

A. 6-({3-[4-(Trifluoroacetyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline, 20b

To a solution of compound 1g (308 mg, 1 mmol), compound 20a (177 mg, 1 mmol), and Et₃N (0.42 mL, 3 mmol) in CH₂Cl₂ (10 mL) was added HATU (570 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 18 h. The resultant mixture was diluted with CH₂Cl₂ and washed with aq. NaHCO₃. The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 2% MeOH/EtOAc+0.5% Et₃N) gave compound 20b (279 mg). LC/MS m/z (M+H⁺) 397.0.

B. 6-([3-piperazin-1-yl]-azetidin-1-yl)carbonyl-1,2,3,4-tetrahydroquinoline, 20c

To a solution of compound 20b (529 mg, 1.33 mmol) in MeOH (10 mL) was added K₂CO₃ (368 mg, 2.66 mmol). The reaction mixture was stirred at room temperature for 30 min. The resultant mixture was filtered, concentrated under reduced pressure, and the resultant residue was partitioned between CH₂Cl₂ and H₂O. The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give compound 20c (370 mg). LC/MS m/z (M+H⁺) 301.0.

C. 6-(3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]-azetidin-1-yl)carbonyl-1,2,3,4-tetrahydroquinoline, Cpd 357

To a solution of compound 20c (370 mg, 1.23 mmol), compound 5c (160 mg, 1.24 mmol), and Et₃N (0.51 mL, 3.69 mmol) in CH₂Cl₂ (10 mL) was added HATU (703 mg, 1.85 mmol). The reaction mixture was stirred at room temperature for 18 h. The resultant mixture was diluted with CH₂Cl₂ and washed with aq. NaHCO₃. The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc+0.5% Et₃N) gave compound 357 (483 mg). ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J=3.0 Hz, 1H), 7.53-7.58 (m, 1H), 7.33 (s, 1H), 7.24-7.30 (m, 1H), 6.39 (d, J=8.1 Hz, 1H), 3.97-4.66 (m, 6H), 3.86 (d, J=18.4 Hz, 2H), 3.35 (t, J=5.4 Hz, 2H), 3.16-3.26 (m, 1H), 2.77 (t, J=6.2 Hz, 2H), 2.39-2.59 (m, 4H), 1.94 (dt, J=11.8, 6.1 Hz, 2H); LC/MS m/z (M+H⁺) 412.0.

Example 21

6-(3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]-azetidin-1-yl)carbonyl 1-[3-(trifluoromethyl)phenyl]carbonyl-1,2,3,4-tetrahydroquinoline, Cpd 358

To a solution of compound 357 (30 mg, 0.073 mmol) in CH₂Cl₂ (1 mL), at 0° C., was added compound 1f (0.013 mL, 0.088 mmol), then Et₃N (0.03 mL, 0.22 mmol). The reaction mixture was stirred at 0° C. for 2 h. The resultant mixture was partitioned between CH₂Cl₂ and H₂O. The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc+0.5% Et₃N) gave compound 358 (42 mg). ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J=3.3 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.61 (s, 1H), 7.52-7.59 (m, 3H), 7.41-7.49 (m, 1H), 7.12 (dd, J=8.3, 1.8 Hz, 1H), 6.73 (d, J=7.8 Hz, 1H), 4.35-4.59 (m, 2H), 4.18-4.26 (m, 2H), 4.01-4.16 (m, 2H), 3.75-3.95 (m, 4H), 3.17-3.26 (m, 1H), 2.90 (t, J=6.6 Hz, 2H), 2.37-2.57 (m, 4H), 2.02-2.12 (m, 2H); LC/MS m/z (M+H⁺) 584.0.

Following the procedure described above for Example 21 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 359 1-(Cyclopropylcarbonyl)-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4- tetrahydroquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J = 3.3 Hz, 1H), 7.55 (d, J = 3.3 Hz, 1H), 7.50 (s, 1H), 7.43-7.47 (m, 2H), 4.05-4.62 (m, 6H), 3.75-3.97 (m, 4H), 3.21-3.31 (m, 1H), 2.78 (t, J = 6.6 Hz, 2H), 2.38-2.59 (m, 4H), 1.90-2.03 (m, 3H), 1.13-1.21 (m, 2H), 0.80-0.86 (m, 2H); LC/MS m/z (M + H⁺) 480.0. 360 1-(Cyclohexylcarbonyl)-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4- tetrahydroquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, J = 3.0 Hz, 1H), 7.55 (d, J = 3.3 Hz, 1H), 7.50 (s, 1H), 7.44 (dd, J = 8.2, 1.6 Hz, 1H), 7.28-7.33 (m, 1H), 4.04-4.62 (m, 6H), 3.73-3.96 (m, 4H), 3.21- 3.30 (m, 1H), 2.72-2.82 (m, 3H), 2.40-2.59 (m, 4H), 1.98 (quin, J = 6.6 Hz, 2H), 1.71-1.83 (m, 4H), 1.49-1.70 (m, 2H), 1.10- 1.36 (m, 4H); LC/MS m/z (M + H⁺) 522.2. 361 1-(Methylsulfonyl)-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4- tetrahydroquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, J = 3.0 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.55 (d, J = 3.3 Hz, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.40 (dd, J = 8.6, 2.3 Hz, 1H), 4.03-4.61 (m, 6H), 3.78-3.96 (m, 4H), 3.21-3.29 (m, 1H), 2.95 (s, 3H), 2.89 (t, J = 6.6 Hz, 2H), 2.40-2.59 (m, 4H), 1.97-2.08 (m, 2H); LC/MS m/z (M + H⁺) 490.0. 362 1-(Methylsulfonyl)-6-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4- tetrahydroquinoline ¹H NMR (400 MHz, CDCl₃): δ 8.79 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 2.3 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.49 (s, 1H), 7.39 (dd, J = 8.7, 2.1 Hz, 1H), 3.72-4.37 (m, 10H), 3.19-3.30 (m, 1H), 2.94 (s, 3H), 2.87 (t, J = 6.6 Hz, 2H), 2.33-2.56 (m, 4H), 1.96-2.04 (m, 2H); LC/MS m/z (M + H⁺) 490.0. 363 1-(Methylsulfonyl)-6-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.73 (d, J = 8.6 Hz, 1H), 7.49 (s, 1H), 7.35-7.44 (m, 6H), 4.00-4.36 (m, 4H), 3.64-3.97 (m, 4H), 3.48 (br. s., 2H), 3.18-3.27 (m, 1H), 2.91-2.97 (m, 3H), 2.87 (t, J = 6.6 Hz, 2H), 2.19-2.56 (m, 4H), 1.97-2.04 (m, 2H); LC/MS m/z (M + H⁺) 483.0. 364 1-(Cyclobutylcarbonyl)-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4- tetrahydroquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J = 3.0 Hz, 1H), 7.55 (d, J = 3.3 Hz, 1H), 7.48 (s, 1H), 7.39-7.44 (m, 1H), 7.24-7.28 (m, 1H), 4.01-4.63 (m, 6H), 3.78-3.97 (m, 2H), 3.67-3.76 (m, 2H), 3.48 (quin, J = 8.4 Hz, 1H), 3.20-3.30 (m, 1H), 2.76 (t, J = 6.3 Hz, 2H), 2.34-2.60 (m, 6H), 2.08 (m, 2H), 1.83-2.02 (m, 4H); LC/MS m/z (M + H⁺) 494.0. 365 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1-(4-trifluoromethylbenzoyl)-1,2,3,4- tetrahydroquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J = 3.3 Hz, 1H), 7.52- 7.61 (m, 4H), 7.49 (d, J = 8.1 Hz, 2H), 7.12-7.18 (m, 1H), 6.75- 6.85 (m, 1H), 4.00-4.60 (m, 6H), 3.76-3.95 (m, 4H), 3.18-3.27 (m, 1H), 2.90 (t, J = 6.6 Hz, 2H), 2.37-2.57 (m, 4H), 2.02-2.12 (m, 2H); LC/MS m/z (M + H⁺) 584.0. 729 2-[(4,4-Difluorocyclohexyl)carbonyl]-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4- tetrahydroisoquinoline MS m/z (M + H⁺) 558.0 679 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-2-{[3-(trifluoromethyl)phenyl]carbonyl}-1,2,3,4- tetrahydroisoquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, J = 3.3 Hz, 1H), 7.70- 7.79 (m, 2H), 7.63-7.68 (m, 1H), 7.57-7.62 (m, 1H), 7.55 (d, J = 3.3 Hz, 1H), 7.50 (s, 1H), 7.45 (br. s., 1H), 7.26 (s, 1H), 4.94 (br. s., 1H), 4.48-4.66 (m, 2H), 4.44 (br. s., 1H), 3.97-4.36 (m, 5H), 3.75-3.96 (m, 2H), 3.65 (br. s., 1H), 3.19-3.33 (m, 1H), 2.85-3.12 (m, 2H), 2.37-2.62 (m, 4H) MS m/z (M + H⁺) 584.0 907 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-2-{[4-(trifluoromethyl)phenyl]carbonyl}-1,2,3,4- tetrahydroisoquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J = 3.3 Hz, 1H), 7.72 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 3.3 Hz, 1H), 7.38-7.52 (m, 2H), 7.21-7.27 (m, 1H), 4.94 (br. s., 1H), 4.48-4.65 (m, 2H), 4.43 (br. s., 1H), 3.95-4.36 (m, 5H), 3.73-3.95 (m, 2H), 3.62 (br. s., 1H), 3.19-3.32 (m, 1H), 2.85- 3.10 (m, 2H), 2.38-2.59 (m, 4H) MS m/z (M + H⁺) 584.0 685 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-2-{[4-(trifluoromethyl)cyclohexyl]carbonyl}- 1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 590.0 736 2-(Phenylcarbonyl)-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4- tetrahydroisoquinoline MS m/z (M + H⁺) 516.0 665 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-2-(thiophen-2-ylcarbonyl)-1,2,3,4- tetrahydroisoquinoline MS m/z (M + H⁺) 522.0 690 2-(1H-Pyrrol-2-ylcarbonyl)-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4- tetrahydroisoquinoline MS m/z (M + H⁺) 505

Example 22

1-(Phenylsulfonyl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline, Cpd 366

To a solution of compound 357 (60 mg, 0.015 mmol) in pyridine (1 mL) was added compound 22a (0.023 mL, 0.017 mmol). The reaction mixture was stirred at room temperature for 2 h. The resultant mixture was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 2% MeOH/EtOAc+0.5% Et₃N) to give compound 366 (66 mg). ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, J=3.3 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.61-7.67 (m, 2H), 7.52-7.59 (m, 2H), 7.36-7.47 (m, 4H), 4.03-4.61 (m, 6H), 3.78-3.93 (m, 4H), 3.20-3.30 (m, 1H), 2.41-2.58 (m, 6H), 1.63-1.71 (m, 2H); LC/MS m/z (M+H⁺) 552.0.

Following the procedure described above for Example 22 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 367 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1,2,3,4- tetrahydroquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.87-7.91 (m, 2H), 7.78-7.86 (m, 3H), 7.57-7.63 (m, 1H), 7.54-7.57 (m, 1H), 7.39-7.45 (m, 2H), 4.07-4.61 (m, 6H), 3.77-3.95 (m, 4H), 3.20-3.30 (m, 1H), 2.41-2.59 (m, 6H), 1.70 (quin, J = 6.3 Hz, 2H); LC/MS m/z (M + H⁺) 620.0. 368 1-[(3-Fluorophenyl)sulfonyl]-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4- tetrahydroquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J = 3.0 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 3.0 Hz, 1H), 7.38-7.47 (m, 4H), 7.32-7.37 (m, 1H), 7.22-7.29 (m, 1H), 4.02-4.61 (m, 6H), 3.77- 3.96 (m, 4H), 3.20-3.30 (m, 1H), 2.40-2.60 (m, 6H), 1.65-1.77 (m, 2H); LC/MS m/z (M + H⁺) 570.0. 369 6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1-[(4-trifluoromethylphenyl)sulfonyl]-1,2,3,4- tetrahydroquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J = 3.3 Hz, 1H), 7.80- 7.85 (m, 1H), 7.73-7.79 (m, 2H), 7.68-7.73 (m, 2H), 7.55 (d, J = 3.3 Hz, 1H), 7.39-7.44 (m, 2H), 4.02-4.61 (m, 6H), 3.77-3.95 (m, 4H), 3.21-3.29 (m, 1H), 2.39-2.59 (m, 6H), 1.65-1.73 (m, 2H); LC/MS m/z (M + H⁺) 620.0 927 2-(Phenylsulfonyl)-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4- tetrahydroisoquinoline MS m/z (M + H⁺) 552.0 928 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-2-{[4-(trifluoromethyl)phenyl]sulfonyl}-1,2,3,4- tetrahydroisoquinoline MS m/z (M + H⁺) 619.8 906 2-(Cyclohexylsulfonyl)-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4- tetrahydroisoquinoline MS m/z (M + H⁺) 558.0

Example 23

1-Benzyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline, Cpd 370

To a solution of compound 357 (30 mg, 0.0073 mmol) in CH₃CN (1 mL) was added compound 18a (0.01 mL, 0.0088 mmol), followed by the addition of K₂CO₃ (20 mg, 0.015 mmol). The reaction mixture was stirred at room temperature for 18 h. The resultant mixture was partitioned between CH₂Cl₂ and H₂O. The organic solution was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 1% MeOH/EtOAc+0.5% Et₃N) gave compound 370 (14 mg). ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J=3.3 Hz, 1H), 7.54 (d, J=3.0 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H), 7.30-7.36 (m, 2H), 7.19-7.30 (m, 4H), 6.44 (d, J=8.6 Hz, 1H), 4.54 (s, 2H), 3.97-4.52 (m, 6H), 3.77-3.96 (m, 2H), 3.40-3.47 (m, 2H), 3.15-3.24 (m, 1H), 2.83 (t, J=6.2 Hz, 2H), 2.38-2.59 (m, 4H), 1.98-2.05 (m, 2H); LC/MS m/z (M+H⁺) 502.2.

Following the procedure described above for Example 23 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 371 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1-(4-trifluoromethylbenzyl)-1,2,3,4- tetrahydroquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J = 3.0 Hz, 1H), 7.59 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 3.0 Hz, 1H), 7.39 (s, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.23-7.29 (m, 1H), 6.35 (d, J = 8.6 Hz, 1H), 4.58 (s, 2H), 3.97-4.54 (m, 6H), 3.74-3.97 (m, 2H), 3.39-3.49 (m, 2H), 3.15-3.26 (m, 1H), 2.85 (t, J = 6.1 Hz, 2H), 2.38-2.59 (m, 4H), 1.99-2.10 (m, 2H); LC/MS m/z (M + H⁺) 570.0. 879 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-2-[3-(trifluoromethyl)benzyl]-1,2,3,4- tetrahydroisoquinoline MS m/z (M + H⁺) 570.0. 880 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-2-[4-(trifluoromethyl)benzyl]-1,2,3,4- tetrahydroisoquinoline MS m/z (M + H⁺) 570.0.

Example 23a

2-Benzyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline, Cpd 680

A solution of Cpd 916 (50 mg, 0.121 mmol) and benzaldehyde 23a (0.014 mL, 0.134 mmol) in CH₂Cl₂ (2 mL) was stirred at room temperature for 30 min Sodium triacetoxyborohydride (38.6 mg, 0.182 mmol) was added and the mixture was stirred overnight. The resulting mixture was combined with CH₂Cl₂ and H₂O, and pH of the water layer was adjusted to pH˜8 with 1N aqueous NaOH. The organic solution was dried over Na₂SO₄ and concentrated. Purification the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc) gave Cpd 680 (38.6 mg). ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, J=3.2 Hz, 1H), 7.55 (d, J=3.2 Hz, 1H), 7.32-7.44 (m, 6H), 7.3 (d, J=8.1 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 4.33-4.63 (m, 2H), 3.99-4.34 (m, 4H), 3.75-3.98 (m, 2H), 3.70 (s, 2H), 3.65 (s, 2H), 3.16-3.30 (m, 1H), 2.93 (t, J=5.7 Hz, 2H), 2.76 (t, J=5.7 Hz, 2H), 2.37-2.60 (m, 4H). MS m/z (M+H⁺) 502.0.

Following the procedure described above for Example 23a, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1458 2-Benzyl-8-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 502.3

Example 24

1-Phenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline, Cpd 372

To a dry Schlenk tube was added a mixture of compound l1 (30 mg; 0.0073 mmol), palladium (II) acetate (1 mg; 0.00037 mmol), BINAP (3 mg; 0.00044 mmol), and KO^(t)Bu (12 mg; 0.01 mmol). The tube, equipped with a teflon-lined septum, was evacuated, and filled with argon. Bromobenzene (14 mg; 0.0088 mmol), and toluene (0.8 mL) were added to the reaction mixture via syringe. The reaction mixture was heated at 110° C. for 21 h. The resultant mixture was diluted with CH₂Cl₂, and washed sequentially with saturated NH₄Cl_((aq)) and H₂O. The organic phase was dried over Na₂SO₄, filtered, and concentrated. Purification of the residue by preparative TLC (silica gel, 2% MeOH/EtOAc+0.5% Et₃N) gave compound 372 (1.3 mg). ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J=3.3 Hz, 1H), 7.55 (d, J=3.0 Hz, 1H), 7.36-7.45 (m, 3H), 7.14-7.26 (m, 4H), 6.55 (d, J=8.6 Hz, 1H), 3.98-4.64 (m, 6H), 3.74-3.96 (m, 2H), 3.61-3.72 (m, 2H), 3.16-3.27 (m, 1H), 2.88 (t, J=6.3 Hz, 2H), 2.37-2.61 (m, 4H), 2.05-2.13 (m, 2H); LC/MS m/z (M+H⁺) 488.0.

Following the procedure described above for Example 24 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 373 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1,2,3,4- tetrahydroquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, J = 3.3 Hz, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 3.0 Hz, 1H), 7.46 (s, 1H), 7.33 (d, J = 8.3 Hz, 2H), 7.24 (dd, J = 8.7, 2.1 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 4.01-4.62 (m, 6H), 3.75-3.98 (m, 2H), 3.64-3.73 (m, 2H), 3.18-3.30 (m, 1H), 2.87 (t, J = 6.3 Hz, 2H), 2.36-2.62 (m, 4H), 2.02-2.12 (m, 2H); LC/MS m/z (M + H⁺) 556.0. 374 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1-[3-(trifluoromethyl)phenyl]-1,2,3,4- tetrahydroquinoline ¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J = 3.0 Hz, 1H), 7.55 (d, J = 3.0 Hz, 1H), 7.37-7.52 (m, 5H), 7.22 (dd, J = 8.6, 2.0 Hz, 1H), 6.66 (d, J = 8.6 Hz, 1H), 4.03-4.59 (m, 6H), 3.74-3.96 (m, 2H), 3.61-3.72 (m, 2H), 3.18-3.27 (m, 1H), 2.89 (t, J = 6.3 Hz, 2H), 2.37-2.60 (m, 4H), 2.03-2.14 (m, 2H); LC/MS m/z (M + H⁺) 556.0. 375 1-Pyrimidin-2-yl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline ¹H NMR (400 MHz, CDCl₃): δ 8.46 (d, J = 4.8 Hz, 2H), 7.89 (d, J = 3.0 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.55 (d, J = 3.3 Hz, 1H), 7.50 (s, 1H), 7.41 (dd, J = 8.6, 2.0 Hz, 1H), 6.75 (t, J = 4.8 Hz, 1H), 4.06-4.61 (m, 6H), 3.99-4.06 (m, 2H), 3.77-3.96 (m, 2H), 3.18-3.29 (m, 1H), 2.83 (t, J = 6.4 Hz, 2H), 2.39-2.59 (m, 4H), 1.99-2.07 (m, 2H); LC/MS m/z (M + H⁺) 490.0. 883 2-Phenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 488.1 668 2-Pyrimidin-2-yl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 490.0 661 2-Pyridin-2-yl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 489.0 805 2-Phenyl-8-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroisoquinoline MS m/z (M + H⁺) 490.1

Example 25

A. 1-Acetyl-6-bromo-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid methyl ester, 25b

To a solution of compound 25a (100 mg, 0.37 mmol) in CH₂Cl₂ (5 mL) was added acetyl chloride (0.1 mL), and pyridine (0.1 mL). The reaction mixture was stirred at room temperature for 2 h. The resultant mixture was partitioned between CH₂Cl₂ and H₂O. The organic phase was dried over Na₂SO₄, filtered, and concentrated to give the crude compound 25b (116 mg), which was used in the next step without further purification. LC/MS m/z 312.0 (M+H⁺), 314.0 (M+2H⁺).

B. 1-Acetyl-6-bromo-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid, 25c

To a solution of compound 25b (116 mg, 0.37 mmol) in THF/MeOH/H₂O (2/2/2 mL) was added LiOH (62 mg, 1.48 mmol). The reaction mixture was stirred at room temperature for 3 h. The resultant mixture was concentrated under reduced pressure, partitioned between CH₂Cl₂ and H₂O, and the aqueous phase was brought to pH 5 by the addition of 2N HCl (aq). The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude compound 25c, which was used in the next step without further purification. LC/MS m/z 298.0 (M+H⁺), 300.0 (M+2H⁺).

C. 1-Acetyl-6-bromo-2-({3-[4-(trifluoroacetyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline, 25d

To a solution of compound 1g (228 mg, 0.74 mmol), compound 25c (22 mg, 0.74 mmol), and Et₃N (0.3 mL, 2.22 mmol) in CH₂Cl₂ (7 mL) was added HATU (338 mg, 0.89 mmol). The reaction mixture was stirred at room temperature for 18 h. The resultant mixture was diluted with CH₂Cl₂ and washed with aqueous NaHCO₃. The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc+0.5% Et₃N) gave compound 25d (265 mg). LC/MS m/z (M+H⁺), 517.0 (M+2H⁺), 519.0.

D. 1-Acetyl-6-bromo-2-({3-[piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline, 25e

To a solution of compound 25d (261 mg, 0.505 mmol) in MeOH (3 mL) was added K₂CO₃ (140 mg, 1.01 mmol). The reaction mixture was stirred at room temperature for 30 min. The resultant mixture was filtered, the filtrate concentrated under reduced pressure, and the resultant residue partitioned between CH₂Cl₂ and H₂O. The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give compound 25e (158 mg). LC/MS m/z (M+H⁺) 421.0, (M+2H⁺) 423.0.

E. 1-Acetyl-6-bromo-2-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline, Cpd 376

The title compound was prepared in an analogous manner to that of compound 357 substituting compound 25e for compound 20c. LC/MS m/z (M+H⁺) 532.0, (M+2H⁺) 534.0.

Following the procedure described above for Example 25 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 377 1-Acetyl-6-bromo-2-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,2,3,4- tetrahydroquinoline LC/MS m/z (M + H⁺) 532.0, (M + 2H⁺) 534.0. 378 1-Acetyl-6-bromo-2-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline LC/MS m/z (M + H⁺) 525.0, (M + 2H⁺) 527.0.

Example 26

A. Tert-Butyl 3-(4-Benzoyl-piperazin-1-yl)-azetidine-1-carboxylate, 4b

To a solution of compound 2a (5 g) and compound 4a (6.75 g) in 1,2 dichloroethane (50 mL) was added AcOH (1.0 mL) and 4 Å molecular sieves. The resultant mixture was stirred for 2 h, at which time NaBH(OAc)₃ (11 g) was added in three portions. The mixture was stirred for 18 h, poured into 2N KOH (aq., 50 mL), and then extracted with EtOAc (3×). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure reduced pressure. The residue was purified by flash column chromatography (5% MeOH/CH₂Cl₂) to give compound 4b (11.6 g).

B. 3-(4-Benzoyl-piperazin-1-yl)-azetidine, HCl salt 2c

To a solution of compound 4b (5.1 g) in CH₂Cl₂ (20 mL) was added TFA (10 mL). The resultant mixture was stirred at room temperature for 4 h. The solvents were removed under reduced pressure. The resultant residue was dissolved in CH₂Cl₂ (5 mL), to which was added 4M HCl in dioxane (3.67 mL). The resulting solid was collected by filtration, washed with ether, and dried under reduced pressure to give compound 2c as its hydrochloride salt (4.0 g).

C. 4-Acetoxy benzoyl chloride, 26b

To a solution of compound 26a (200 mg, 1.11 mmol) in THF (5 mL) was added oxalyl dichloride (97 μL, 1.11 mmol) dropwise at 0° C., followed by the addition of 2 drops of DMF. The resultant mixture was stirred at 0° C. for 3 h, and then warmed to room temperature for 18 h. The solvents were removed under reduced pressure and the crude residue, compound 26b, was dried under reduced pressure for 2 h, and used in the next step without further purification.

D. 4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl acetate (26c)

To a mixture of the HCl salt of compound 2c (373 mg, 1.33 mmol), Et₃N (0.5 mL) and CH₂Cl₂ (5 mL) was added a solution of compound 26b in CH₂Cl₂ (1 mL). The resultant mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure, the residue dissolved in CH₂Cl₂ (1 mL), and then purified by flash column chromatography (silica gel, 5% MeOH/CH₂Cl₂) to give compound 26c (442 mg).

E. 4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenol, 26d

A mixture of compound 26c (420 mg, 1.03 mmol) and LiOH (100 mg, 4.0 mmol) in a solvent mixture of THF/MeOH/H₂O (2/2/2 mL) was stirred at room temperature for 4 h, at which time it was brought to pH 5 by the addition of 2N HCl (aq). The mixture was extracted with EtOAc (3×). The combined extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resultant residue (crude compound 26d) was dried under reduced pressure for 18 h, and used in the following step without further purification.

F. 1-[1-({4-[(3,4-dichlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine, Cpd 379

A mixture of compound 26d (70 mg, 0.191 mmol), K₂CO₃ (53 mg, 0.382 mmol), compound 26e (68 mg, 0.287 mmol) and DMF (3 mL) was stirred at room temperature for 18 h. Water was added to the reaction mixture and the mixture was extracted with EtOAc (3×). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography, eluting with 5% MeOH/CH₂Cl₂ to give compound 379 (83 mg). ¹H NMR (CDCl₃): δ 7.59-7.64 (d, J=8.8 Hz, 2H), 7.53 (d, J=2.0 Hz, 1H), 7.455 (d, J=8.0 Hz, 1H), 7.37-7.44 (m, 5H), 7.23-7.28 (m, 2H), 6.955 (d, J=8.84 Hz, 2H), 5.05 (s, 2H), 4.31 (br. s., 1H), 4.11-4.27 (m, 2H), 4.00-4.10 (m, 1H), 3.91 (br. s., 1H), 3.64-3.82 (m, 1H), 3.48 (br. s., 2H), 3.18-3.27 (m, 1H), 2.42 (br. s., 4H). MS m/z (M+H⁺) 524.0.

Following the procedure described above for Example 26 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 380 1-(1-{[4-(Naphthalen-2-ylmethoxy)phenyl]carbonyl}azetidin-3- yl)-4-(phenylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.80-7.88 (m, 4H), 7.59-7.64 (m, J = 8.8 Hz, 2H), 7.45-7.53 (m, 3H), 7.36-7.43 (m, 5H), 7.00 (d, J = 8.8 Hz, 2H), 5.22 (s, 2H), 4.24-4.32 (m, 1H), 4.08-4.24 (m, 2H), 4.03 (br. s., 1H), 3.60-3.79 (m, 1H), 3.31-3.52 (m, 2H), 3.10-3.22 (m, 1H), 2.38 (br. s., 4H). MS m/z (M + H⁺) 506.2 381 1-[1-({4-[(2,3-Dichlorobenzyl)oxy]phenyl}carbonyl)azetidin-3- yl]-4-(phenylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.625 (d, J = 8.4 Hz, 2H), 7.44 (dd, J = 8.0, 2.1 Hz, 2H), 7.37-7.41 (m, 5H), 7.23 (t, J = 8.1, 1H), 6.97 (d, J = 8.8 Hz, 2H), 5.18 (s, 2H), 4.26-4.36 (m, 1H), 4.12-4.26 (m, 2H), 4.07 (br. s, 1H), 3.88 (br. s., 1H), 3.74 (br. s., 1H), 3.47 (br. s., 2H), 3.14-3.27 (m, 1H), 2.41 (br. s., 3H), 2.22 (s, 1H). MS m/z (M + H⁺) 524.0 382 1-[1-({4-[(4-Fluorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]- 4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 474.2 383 1-(Phenylcarbonyl)-4-{1-[(4-{[4- (trifluoromethyl)benzyl]oxy}phenyl)carbonyl]azetidin-3- yl}piperazine MS m/z (M + H⁺) 524.2 384 1-[1-({4-[(4-Chlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]- 4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 490.2 385 1-[1-({4-[(2,4-Dichlorobenzyl)oxy]phenyl}carbonyl)azetidin-3- yl]-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 524.1 386 4-{[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenoxy]methyl}benzonitrile MS m/z (M + H⁺) 481.2 387 1-[1-({4-[2-(4-Chlorophenyl)ethoxy]phenyl}carbonyl)azetidin- 3-yl]-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 504.2 388 1-[1-({4-[2-(4-Fluorophenyl)ethoxy]phenyl}carbonyl)azetidin- 3-yl]-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 488.2 389 1-(Phenylcarbonyl)-4-(1-{[4-({4- [(trifluoromethyl)sulfanyl]benzyl}oxy)phenyl]carbonyl}azetidin- 3-yl)piperazine MS m/z (M + H⁺) 556.2 390 1-(Phenylcarbonyl)-4-{1-[(4-{[4- (trifluoromethoxy)benzyl]oxy}phenyl)carbonyl]azetidin-3- yl}piperazine MS m/z (M + H⁺) 540.2 391 1-[1-({4-[(3-Chlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]- 4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 490.2 392 1-[1-({4-[(3-Chloro-4- fluorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 508.2 393 1-(Phenylcarbonyl)-4-{1-[(4-{[3- (trifluoromethoxy)benzyl]oxy}phenyl)carbonyl]azetidin-3- yl}piperazine MS m/z (M + H⁺) 540.2 394 4-[(4-{[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenoxy]methyl}phenyl)sulfonyl]morpholine MS m/z (M + H⁺) 605.2 395 1-{1-[(4-{[3-Fluoro-4- (trifluoromethyl)benzyl]oxy}phenyl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 542.2 396 1-(Phenylcarbonyl)-4-(1-{[4-(pyridin-4- ylmethoxy)phenyl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 457.2

Example 27

A. Methyl 4-(3-chlorobenzyloxy)-3-chlorobenzoate, 27c

A mixture of compound 27a (500 mg, 2.7 mmol), compound 27b (0.53 mL, 4.03 mmol), and K₂CO₃ (745 mg, 5.4 mmol) in DMF was stirred at room temperature for 18 h. Water was added to the reaction mixture and the mixture was extracted with EtOAc (3×). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resultant residue was purified by silica gel flash column chromatography, eluting with 30% EtOAc/hexanes to give compound 27c (662 mg).

B. 4-(3-Chlorobenzyloxy)-3-chlorobenzoic acid, 27d

A mixture of compound 27c (662 mg, 2.0 mmol) and LiOH (192 mg, 8 mmol) in a solvent mixture of THF/MeOH/H₂O (3/3/3 mL) was stirred at room temperature for 4 h, then acidified with 15% citric acid in H₂O. The mixture was extracted with EtOAc (3×), and the combined extracts washed sequentially with water and brine. The extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resultant crude compound 3b was dried under reduced pressure for 18 h and used in the following reaction without further purification.

C. 4-(3-Chlorobenzyloxy)-3-chlorobenzoyl chloride, 27e

To a solution of compound 27d (67 mg, 0.33 mmol) in THF (2 mL) was added oxalyl dichloride (43 μL, 0.50 mmol) dropwise at 0° C., followed by the addition of 2 drops of DMF. The resultant mixture was stirred at 0° C. for 3 h, and then was warmed up to room temperature over 18 h. The solvents were removed under reduced pressure. The resultant residue, crude compound 27e, was dried under reduced pressure for 2 h and used in the following step without further purification.

D. 1-[1-({3-Chloro-4-[(3-chlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine, Cpd 397

To a mixture of compound 2c (84 mg, 0.30 mmol), Et₃N (0.5 mL), and CH₂Cl₂ (2.5 mL) was added a solution of compound 27e in CH₂Cl₂ (1 mL). The resultant mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure. The resultant residue was dissolved in CH₂Cl₂ (1 mL), loaded on a silica gel column, and purified by flash column chromatography, eluting with 5% MeOH/CH₂Cl₂ to give compound 397 (32 mg). ¹H NMR (CDCl₃): δ 7.695 (d, 1H, J=2.0 Hz), 7.515 (dd, 1H, J=2.0 Hz, J2=8.6 Hz), 7.44 (s, 1H), 7.38-7.43 (m, 5H), 7.30-7.35 (m, 3H), 6.91-6.97 (d, 1H, J=8.6 Hz), 5.15 (s, 2H), 4.26-4.37 (m, 1H), 4.15-4.26 (m, 2H), 3.84-3.98 (m, 1H), 3.68-3.82 (m, 1H), 3.48 (br. s., 2H), 3.18-3.29 (m, 1H), 2.56-2.16 (m, 4H). MS m/z (M+H⁺) 524.0.

Following the procedure described above for Example 27 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 398 1-(1-{[3-Chloro-4-(pyridin-4- ylmethoxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 8.64 (d, J = 5.8 Hz, 2H), 7.2 (d, J = 2.0 Hz, 1H), 7.53 (dd, J1 = 2.1, 8.4 Hz, 1H), 7.36-7.45 (m, 7H), 6.88-6.95 (d, J = 8.6 Hz, 1H), 5.19 (s, 2H), 4.27-4.37 (m, 1H), 4.11-4.27 (m, 2H), 3.99-4.08 (m, 1H), 3.81-3.96 (m, 1H), 3.73 (br. s, 1H), 3.48 (br. s., 2H), 3.17-3.30 (m, 1H), 2.41 (br. s., 4H). MS m/z (M + H⁺) 498.0 399 1-[1-({3-Chloro-4-[(3,4- dichlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.70 (d, J = 2.0 Hz, 1H), 7.56 (s, 1H), 7.53 (dd, J = 8.6, 2.0 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.37-7.44 (m, 5H), 7.28-7.32 (m, 1H), 6.93 (d, J = 8.2 Hz, 1H), 5.14 (s, 2H), 4.28-4.37 (m, 1H), 4.12-4.27 (m, 2H), 4.05 (br. s., 1H), 3.91 (br. s., 1H), 3.74 (br. s., 1H), 3.49 (br. s., 2H), 3.16-3.27 (m, 1H), 2.42 (br. s., 4H). MS m/z (M + H⁺) 558.0 400 1-[1-({4-[(3,4-Dichlorobenzyl)oxy]-3 fluorophenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.88 (d, J = 3.3 Hz, 1H), 7.53-7.57 (m, 2H), 7.41-7.48 (m, 2H), 7.39 (dd, J = 8.5, 1.1 Hz, 1H), 7.25-7.30 (m, 1H), 6.97 (t, J = 8.3 Hz, 1H), 5.12 (s, 2H), 4.52 (br. d., J = 33.8 Hz, 1H), 4.37-4.47 (m, 1H), 4.32 (d, J = 6.8 Hz, 1H), 4.15-4.28 (m, 2H), 4.07 (d, J = 8.3 Hz, 1H), 3.85 (d, J = 17.4 Hz, 2H), 3.20-3.28 (m, 1H), 2.48 (t, J = 4.8 Hz, 4H). MS m/z (M + H⁺) 549.0. 401 1-[1-({3-Chloro-4-[(3- chlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3- thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.88 (d, J = 3.3 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.50-7.57 (m, 2H), 7.45 (s, 1H), 7.30-7.35 (m, 3H), 6.95 (d, J = 8.6 Hz, 1H), 5.17 (s, 2H), 4.43 (br. s., 1H), 4.28-4.38 (m, 1H), 4.17-4.28 (m, 1H), 4.03-4.15 (m, 2H), 3.85 (d, J = 19.5 Hz, 2H), 3.19-3.29 (m, 1H), 2.48 (m, 4H). MS m/z (M + H⁺) 531.0 402 1-(1-{[3-Chloro-4-(pyridin-3- ylmethoxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 8.71 (s, 1H), 8.61 (d, J = 3.5 Hz, 1H), 7.88 (d, J = 3.0 Hz), 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 3.6 Hz, 1H), 7.36 (dd, J = 7.8, 4.8 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 5.21 (s, 2H), 4.52 (br. S, 1H), 4.43 (br. S, 1H), 4.32 (m, 1H), 4.16-4.29 (m, 2H), 4.03-4.16 (m, 1H), 3.76-3.95 (m, 2H), 3.20-3.30 (m, 1H), 2.57-2.36 (m, 4H). MS m/z (M + H⁺) 498.0. 403 1-(1-{[4-(Pyridin-4-ylmethoxy)phenyl]carbonyl}azetidin-3-yl)- 4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 8.63 (d, J = 5.8 Hz, 2H), 7.88 (d, J = 3.0 Hz, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 3.3 Hz, 1H), 7.36 (d, J = 6.1 Hz, 2H), 6.96 (d, J = 8.84 Hz, 2H), 5.14 (s, 2H), 4.52 (br. s, 1H), 4.43 (br. s, 1H), 4.36-4.29 (m, 1H), 4.16-4.29 (m, 2H), 4.04-4.16 (m, 1H), 3.75-3.93 (m, 2H), 3.18-3.28 (m, 1H), 2.37-2.58 (m, 4H). MS m/z (M + H⁺) 464.0 404 1-[1-({3-Chloro-4-[(3,4- dichlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3- thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.88 (d, J = 3.0 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.51-7.58 (m, 3H), 7.47 (dd, J = 8.3, 4.0 Hz, 1H), 7.30 (dd, J = 8.1, 2.0 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 5.14 (s, 2H), 4.52 (br. s., 1H), 4.37 (br. s., 1H), 4.29-4.37 (m, 1H), 4.22 (br. s., 2H), 4.01-4.14 (m, 1H), 3.88 (br. s., 2H), 3.19-3.32 (m, 1H), 2.40-2.55 (m, 4H) MS m/z (M + H⁺) 564.6, 566.8 405 1-[1-({4-[(2,3-Dichlorobenzyl)oxy]-3- fluorophenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.88 (d, J = 3.3 Hz, 1H), 7.55 (d, J = 3.3 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.43-7.46 (m, 1H), 7.40 (dd, J = 8.6, 1.3 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.00 (t, J = 8.3 Hz, 1H), 5.28 (s, 2H), 4.49 (d, J = 33.2 Hz, 2H), 4.31-4.39 (m, 1H), 4.22 (br. s., 2H), 4.03-4.16 (m, 1H), 3.88 (br. s., 2H), 3.19-3.31 (m, 1H), 2.40-2.58 (m, 4H). MS m/z (M + H⁺) 549.0 406 1-(1-{[3-Chloro-4-(pyridin-2- ylmethoxy)phenyl]carbonyl}azetidin-3-yl)-4- (phenylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 8.59 (d, J = 4.5 Hz, 1H), 7.76 (dd, J = 1.5, 7.6 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.50 (dd, J = 8.6, 2.0 Hz, 1H), 7.37-7.44 (m, 5H), 7.25 (dd, J = 6.9, 5.2 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 5.28-5.35 (m, 2H), 4.27-4.37 (m, 1H), 4.12-4.27 (m, 2H), 3.99-4.12 (m, 1H), 3.89 (br. s., 1H), 3.74 (br. s., 1H), 3.47 (br. s., 2H), 3.17-3.27 (m, 1H), 2.42 (br. s., 3H), 2.27 (br. s., 1H). 407 1-(1-{[3-Chloro-4-(pyridine-2- ylmethoxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 8.54 (br. s, 1H), 8.49 (br. s, 1H), 7.62-7.68 (m, 1H), 7.53 (d, J = 8.6 Hz, 2H), 7.37-7.44 (m, 5H), 7.29 (d, J = 9.1 Hz, 2H), 7.23 (dd, J = 7.8, 4.8 Hz, 1H), 4.17-4.32 (m, 2H), 4.09-4.17 (m, 3H), 4.00-4.08 (m, 1H), 3.89 (br. s., 1H), 3.74 (br. s, 1H), 3.47 (br. s, 2H), 3.15-3.28 (m, 1H), 2.41 (br. s., 3H), 2.17 (br. s, 1H) MS m/z (M + H⁺) 498.0 408 1-(1-{[3-Chloro-4-(pyridin-4- ylmethoxy)phenyl]carbonyl}azetidin-3-yl)-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 491.2 409 1-(1-{[3-Chloro-4-(pyridin-3- ylmethoxy)phenyl]carbonyl}azetidin-3-yl)-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 491.2 481 1-[1-({4-[(4-Chlorobenzyl)oxy]-3- fluorophenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 508.2 482 1-[1-({4-[(3,4-Dichlorobenzyl)oxy]-3- fluorophenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 542.1 483 1-[1-({4-[(2,3-Dichlorobenzyl)oxy]-3- fluorophenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 542.1 484 1-[1-({4-[(4-Chlorobenzyl)oxy]-3- iodophenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 616.1 972 1-[1-({4-[(5-Chlorothiophen-2- yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 496.0 560 2-{[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenoxy]methyl}quinoline MS m/z (M + H⁺) 507.0 552 1-[1-({4-[(6-Bromopyridin-2- yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 535.0 957 1-[1-({4-[(3-Chlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]- 4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 497.0 962 1-[1-({4-[(5-Chlorothiophen-2- yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 503.0 967 2-{[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)phenoxy]methyl}quinoline MS m/z (M + H⁺) 514.0 983 1-[1-({4-[(6-Bromopyridin-2- yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 543.8 960 1-[1-({4-[(3-Chlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]- 4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 497.0 963 1-[1-({4-[(5-Chlorothiophen-2- yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 503.0 970 2-{[4-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)phenoxy]methyl}quinoline MS m/z (M + H⁺) 514.0 987 1-[1-({4-[(6-Bromopyridin-2- yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 542.0

Example 27a

E. Methyl 4-((5-chloropyridin-3-yl)methoxy)benzoate, 27b

DIAD (2.35 mmol, 0.45 mL) was added to an ice-cold solution of methyl 4-hydroxybenzoate 29a (2.35 mmol, 358 mg), (5-chloropyridin-3-yl)methanol 27a (1.57 mmol, 225 mg), and Ph₃P (2.35 mmol, 616 mg) in 8 mL of THF. The mixture was stirred at 0° C. for 1 h at room temperature overnight. Water was added and the crude product was purified by flash column chromatography (silica gel, 20% EtOAc/hexanes) to afford 300 mg (68%) of 27b.

F. 4-((5-Chloropyridin-3-yl)methoxy)benzoic acid, 27c

Compound 27b (1.22 mmol, 340 mg) was combined with LiOH (4.9 mmol, 118 mg) in 3 mL of THF, 3 mL of MeOH, and 3 mL of water. The mixture was stirred at room temperature for 4 h and was then combined with 15% aqueous citric acid and extracted with EtOAc. The extracts were washed with water and brine, dried over Na₂SO₄, and concentrated under vacuum to give 288 mg of 27c.

Following the procedure described above for Example 1 or Example 27, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 554 1-[1-({4-[(5-Chloropyridin-3- yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 491.0 978 1-[1-({4-[(5-Chloropyridin-3- yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol- 2-ylcarbonyl)piperazine MS m/z (M + H⁺) 498.0 981 1-[1-({4-[(5-Chloropyridin-3- yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol- 4-ylcarbonyl)piperazine MS m/z (M + H⁺) 498.0

Example 27b

Following the procedure described above for Example 1c, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Salt Cpd Cpd Name and Data Form 958 1-[1-({4-[(3- N-TFA Chlorobenzyl)oxy]phenyl}carbonyl)azetidin-3-yl]- 4-(trifluoroacetyl)piperazine MS m/z (M + H⁺) 482.0 961 1-[1-({4-[(5-Chlorothiophen-2- N-TFA yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4- (trifluoroacetyl)piperazine MS m/z (M + H⁺) 488.0 968 2-{[4-({3-[4-(Trifluoroacetyl)piperazin-1- N-TFA yl]azetidin-1- yl}carbonyl)phenoxy]methyl}quinoline MS m/z (M + H⁺) 499.0 979 1-[1-({4-[(5-Chloropyridin-3- N-TFA yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4- (trifluoroacetyl)piperazine 984 1-[1-({4-[(6-Bromopyridin-2- N-TFA yl)methoxy]phenyl}carbonyl)azetidin-3-yl]-4- (trifluoroacetyl)piperazine MS m/z (M + H⁺) 535.0

Example 28

A. Methyl 4-(3-chlorobenzylsulfanyl)benzoate, 28b

The title compound 28c was prepared using the method described in Example 27, substituting compound 28a for compound 27a in Procedure A.

B. 4-(3-Chlorobenzylsulfanyl)benzoic acid, 28c

The title compound 28c was prepared using the method described in Example 27, substituting compound 28b for compound 27c in Procedure B.

C. 4-(3-Chlorobenzylsulfanyl)benzoyl chloride, 28d

The title compound 28d was prepared using the method described in Example 27, substituting compound 28c for compound 27d in Procedure C.

D. 1-[1-({4-[(3-Chlorobenzyl)sulfanyl]phenyl}carbonyl)azetidi-3-yl]-4-(phenylcarbonyl)piperazine, Cpd 410

The title compound 410 was prepared using the method described in Example 27, substituting compound 28d for compound 27e in Procedure D. ¹H NMR (CDCl₃): δ 7.52 (d, J=8.6 Hz, 2H), 7.37-7.44 (m, 5H), 7.24-7.29 (m, 3H), 7.18-7.24 (m, 3H), 4.18-4.33 (m, 2H), 4.09-4.17 (m, 3H), 4.01-4.08 (m, 1H), 3.92 (br. S, 1H), 3.74 (br. s., 1H), 3.35-3.63 (m, 2H), 3.17-3.29 (m, 1H), 2.20-2.50 (m, 4H); MS m/z (M+H⁺) 506.0.

Following the procedure described above for Example 28 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 411 1-[1-({4-[(2,3- Dichlorobenzyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.52 (d, J = 8.3 Hz, 2H), 7.38-7.43 (m, 5H), 7.29 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 7.1 Hz, 1H), 7.2 (d, J = 7.4 Hz, 1H), 7.11 (q, J = 7.8 Hz, 1H), 4.24-4.38 (m, 4H), 4.22 (br. s., 1H), 4.12-4.21 (m, 1H), 4.02-4.12 (m, 1H), 3.91 (br. s., 1H), 3.77 (br. s., 1H), 3.47 (s, 2H), 3.15-3.29 (m, 1H), 2.44 (br. s., 4H). MS m/z (M + H⁺) 540.0 412 1-[1-({4-[(3-Chlorobenzyl)sulfanyl]phenyl}carbonyl)azetidin- 3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.88 (d, J = 3.3 Hz, 1H), 7.49-7.57 (m, 3H), 7.25-7.30 (m, 3H), 7.18-7.25 (m, 3H), 4.51 (br. s., 2H), 4.21-4.34 (m, 2H), 4.03-4.21 (m, 4H), 3.72-3.94 (m, 2H), 3.18-3.29 (m, 1H), 2.35-2.59 (m, 4H). MS m/z (M + H⁺) 513.0 413 1-[1-({4-[(2,3- Dichlorobenzyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]-4- (1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.88 (d, J = 3.0 Hz, 1H), 7.50-7.57 (m, 3H), 7.38 (dd, J = 7.8, 1.5 Hz, 1H), 7.26-7.33 (m, 3H), 7.22 (dd, J = 7.7, 1.4 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 4.44 (br. d., J = 32.6 Hz, 2H), 4.22-4.35 (m, 4H), 4.15-4.22 (m, 1H), 4.04-4.15 (m, 1H), 3.85 (d, J = 17.4 Hz, 2H), 3.19-3.29 (m, 1H), 2.37-2.56 (m, 4H). MS m/z (M + H⁺) 547.0. 414 1-[1-({4-[(3,4- Dichlorobenzyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]-4- (1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.88 (d, J = 3.3 Hz, 1H), 7.54 (d, J = 3.3 Hz, 2H), 7.51-7.53 (m, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.24-7.29 (m, 3H), 7.13-7.17 (m, 1H), 4.48-4.59 (m, 1H), 4.35-4.48 (m, 1H), 4.20-4.34 (m, 2H), 4.13-4.20 (m, 1H), 4.01-4.13 (m, 4H), 3.79-3.94 (m, 2H), 3.19-3.29 (m, 1H), 2.37-2.57 (m, 4H). MS m/z (M + H⁺) 547.0. 415 1-[1-({4-[(4-Chlorobenzyl)sulfanyl]phenyl}carbonyl)azetidin- 3-yl]-4-(1,3-thiazol-2-ylcarboyl)piperazine ¹H NMR (CDCl₃): δ 7.87 (d, J = 3.3 Hz, 1H), 7.55 (d, J = 3.3 Hz, 1H), 7.53 (d, J = 8.6 Hz, 2H), 7.27-7.29 (m, 2H), 7.24-7.27 (m, 4H), 4.51 (br. s., 1H), 4.35-4.47 (m, 1H), 4.20-4.33 (m, 2H), 4.02-4.20 (m, 4H), 3.76-3.93 (m, 2H), 3.18-3.28 (m, 1H), 2.38-2.54 (m, 4H). MS m/z (M + H⁺) 513.0 416 1-[1-({4-[(Pyridin-3- ylmethyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3- thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 8.55 (s, 1H), 8.48 (s, 1H), 7.82-7.93 (m, 1H), 7.65 (br. s., 1H), 7.47-7.60 (m, 3H), 7.18-7.36 (m, 3H), 4.44 (d, J = 33.9 Hz, 2H), 4.03-4.32 (m, 5H), 3.86 (br. s., 2H), 3.23 (br. s., 1H), 2.47 (br. s., 4H) 417 1-[1-({4-[(3,4- Dichlorobenzyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 540.1 418 1-[1-({4-[(4-Chlorobenzyl)sulfanyl]phenyl}carbonyl)azetidin- 3-yl]-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 506.2 555 1-(Phenylcarbonyl)-4-[1-({4-[(pyridin-3- ylmethyl)sulfanyl]phenyl}carbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 473.0 550 1-(Phenylcarbonyl)-4-{1-[(4-{[3- (trifluoromethyl)benzyl]sulfanyl}phenyl)carbonyl]azetidin-3- yl}piperazine MS m/z (M + H⁺) 540.0 973 1-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(4-{[3- (trifluoromethyl)benzyl]sulfanyl}phenyl)carbonyl]azetidin-3- yl}piperazine MS m/z (M + H⁺) 547.0 975 1-(1,3-Thiazol-4-ylcarbonyl)-4-{1-[(4-{[3- (trifluoromethyl)benzyl]sulfanyl}phenyl)carbonyl]azetidin-3- yl}piperazine MS m/z (M + H⁺) 531.8

Example 28a

Following the procedure described above for Example 1c, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Salt Cpd Cpd Name and Data Form 974 1-(Trifluoroacetyl)-4-{1-[(4-{[3- N-TFA (trifluoromethyl)benzyl]sulfanyl}phenyl)carbonyl] azetidin-3-yl}piperazine MS m/z (M + H⁺) 532.0

Example 29

A. Methyl 4-(3-trifluoromethyl-phenoxy)-benzoate, 29c

To a solution of compound 29a (400 mg, 2.63 mmol) and compound 29b (1.0 g, 5.26 mmol) in CH₂Cl₂ (24 mL) was added Cu(OAc)₂ (714 mg, 3.94 mmol), 4A sieves (400 mg, powder, activated), pyridine (2 mL), and Et₃N (2 mL). The resultant reaction mixture was stirred at room temperature for 2 days. Water was added to the mixture, and the mixture was filtered. The filtrate was extracted with EtOAc (3×), the combined organic extracts dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography, eluting with 20% EtOAc/hexanes to give compound 29c (470 mg).

B. 4-(3-Trifluoromethyl-phenoxy)-benzoic acid (29d)

A mixture of compound 29c (577 mg, 1.95 mmol) and LiOH (187 mg, 7.80 mmol) in THF/MeOH/H₂O (4/4/4 mL) was stirred for 4 h. A 15% citric acid solution (20 mL) was added, and the mixture was then extracted with EtOAc (3×). The combined extracts were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue, compound 29d, was dried under reduced pressure for 18 h and was used without purification.

C. 4-(3-Trifluoromethyl-phenoxy)-benzoyl chloride, 29e

To a solution of compound 29d (100 mg, 0.35 mmol) in THF (2 mL) was added oxalyl dichloride (46 μL, 0.53 mmol) dropwise at 0° C., followed by addition of 2 drops of DMF. The resulting mixture was stirred at 0° C. for 3 h, and was then warmed up to room temperature overnight. The solvents were removed under reduced pressure, and the residue, compound 29e, was dried under reduced pressure for 2 h and then used in the next step without further purification.

D. 1-(Phenylcarbonyl)-4-[1-({4-[3-(trifluoromethyl)phenoxy]phenyl}carbonyl)azetidin-3-yl]piperazine, Cpd 419

To a mixture of compound 2c (80 mg, 0.32 mmol), Et₃N (0.5 mL), and CH₂Cl₂ (2.5 mL) was added a solution of compound 29e in CH₂Cl₂ (1 mL). The resultant mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure, and the resultant residue was dissolved in CH₂Cl₂ (1 mL), directly loaded onto a silica gel column, and purified by silica gel flash column chromatography with 5% MeOH/CH₂Cl₂ to give compound 419 (53 mg). ¹H NMR (CDCl₃): δ 7.65 (d, J=8.6 Hz, 2H), 7.45-7.53 (m, 1H), 7.41 (br. s., 6H), 7.25-7.34 (m, 1H), 7.17-7.25 (m, 1H), 7.01 (d, J=7.3 Hz, 2H), 4.17-4.38 (m, 3H), 4.11 (br. s., 1H), 3.92 (br. s., 1H), 3.78 (br. s., 1H), 3.49 (br. s, 2H), 3.19-3.32 (m, 1H), 2.45 (br. s., 4H). MS m/z (M+H⁺) 510.0.

Following the procedure described above for Example 29 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 420 1-(1-{[4-(4-Chlorophenoxy)phenyl]carbonyl}azetidin-3-yl)-4- (1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.88 (d, J = 3.0 Hz, 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 3.0 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 4H), 4.52 (br. s., 1H), 4.38-4.48 (br. S, 1H), 4.15-4.37 (m, 3H), 4.10 (br. s., 1H), 3.88 (br. s., 1H), 3.82 (br. s., 1H), 3.19-3.31 (m, 1H), 2.35-2.60 (m, 4H). MS m/z (M + H⁺) 483.1 421 1-(1-{[4-(3-Chlorophenoxy)phenyl]carbonyl}azetidin-3-yl)-4- (1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.88 (d, J = 3.3 Hz, 1H), 7.65 (tt, J1 = 2 Hz, J2 = 8.8 Hz, 2H), 7.545 (d, J = 3.3 Hz, 1H), 7.26-7.30 (m, 1H), 7.14 (dt, J = 8.1, 1.0 Hz, 1H), 6.98-7.06 (m, 3H), 6.93-6.95 (m, 1H), 6.91-6.95 (m, 1H), 4.56 (br.s, 1H), 4.43 (br. s., 1H), 4.17-4.38 (m, 3H), 4.04-4.16 (m, 1H), 3.75-3.96 (m, 2H), 3.20-3.31 (m, 1H), 2.39-2.60 (m, 4H). MS m/z (M + H⁺) 483.0 422 1-(1-{[4-(3,4-Dichlorophenoxy)phenyl]carbonyl}azetidin-3-yl)- 4-(phenylcarbonyl)piperazine. ¹H NMR (CDCl₃): δ 7.65 (d, J = 8.6 Hz, 2H), 7.37-7.46 (m, 6H), 7.12 (d, J = 2.8 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 6.89 (dd, J = 8.8, 2.8 Hz, 1H), 4.16-4.37 (m, 3H), 4.10 (br. s., 1H), 3.92 (br. s., 1H), 3.68-3.84 (m, 1H), 3.46 (s, 2H), 3.19-3.30 (m, 1H), 2.44 (br. s., 4H). MS m/z (M + H⁺) 510.0 423 1-(1-{[4-(3,4-Dichlorophenoxy)phenyl]carbonyl}azetidin-3-yl)- 4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.88 (d, J = 3.3 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 3.3 Hz, 1H), 7.42 (d J = 8.8 Hz, 1H), 7.13 (d, J = 2.8 Hz, 1H), 7.0 (d, J = 8.6 Hz, 2H), 6.90 (dd, J = 8.8, 2.8 Hz, 1H), 4.53 (br. s., 1H), 4.44 (br. S, 1H), 4.17-4.38 (m, 3H), 4.11 (dd, J = 9.0, 4.7 Hz, 1H), 3.88 (br. s., 1H), 3.83 (br. s., 1H), 3.20-3.32 (m, 1H), 2.50 (t, J = 4.7 Hz, 4H). MS m/z (M + H⁺) 517.0 424 1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[3- (trifluoromethyl)phenoxy]phenyl}carbonyl)azetidin-3- yl]piperazine ¹H NMR (CDCl₃): δ 7.88 (d, J = 3.3 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 3.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.03 (d, J = 8.6 Hz, 2H), 4.53 (br. s., 1H), 4.44 (br. s, 1H), 4.17-4.38 (m, 3H), 4.16-4.05 (m, 1H), 3.86 (d, J = 19.2 Hz, 2H), 3.20-3.33 (m, 1H), 2.37-2.60 (m, 4H). MS m/z (M + H⁺) 517.0 425 1-(1-{[4-(4-Chlorophenoxy)phenyl]carbonyl}azetidin-3-yl)-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 476.2 426 1-(1-{[4-(3-Chlorophenoxy)phenyl]carbonyl}azetidin-3-yl)-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 476.2 662 1-(1-{[4-(3-Chlorophenoxy)-3-fluorophenyl]carbonyl}azetidin- 3-yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 500.8

Example 29a

Following the procedure described above for Example 1c, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data Salt Form 931 1-(1-{[4-(3-Chlorophenoxy)-3- N-TFA fluorophenyl]carbonyl}azetidin-3-yl)-4- (trifluoroacetyl)piperazine MS m/z (M + H⁺) 485.8

Example 30

A. Methyl 4-(3-chloro-phenylsulfanyl)-benzoate (30c)

A mixture of compound 30a (400 mg, 1.86 mmol), compound 30b (321 mg, 2.23 mmol), Pd(PPh₃)₄ (215 mg, 0.186 mmol), KOtBu (2.23 mL, 2.23 mmol, 1M solution in THF), and THF (3.5 mL) were heated in a microwave reactor at 130° C. for 2 h, then poured into water (50 mL). The mixture was extracted with EtOAc (3×). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography, eluting with 5% EtOAc/hexanes to give compound 30c (220 mg).

B. 4-(3-Chloro-phenylsulfanyl)benzoic acid (30d)

A mixture of compound 30c (320 mg, 1.15 mmol), LiOH (110 mg, 4.59 mmol) in THF/MeOH/H₂O (3/3/3 mL) was stirred for 4 h. A 15% aqueous citric acid solution (10 mL) was added. The mixture was then extracted with EtOAc (3×). The combined organic extracts were washed with brine, filtered, dried over Na₂SO₄, and concentrated under reduced pressure. The resultant residue (compound 30d, 290 mg) was dried under reduced pressure for 18 h and was used without further purification.

C. 4-(1-{[4-(3-Chloro-phenylsulfanyl)phenyl]carbonyl}azetidin-3-yl)-1-(phenylcarbonyl)-piperazine, Cpd 427

A mixture of compound 30d (60 mg, 0.23 mmol), compound 2c (83 mg, 0.29 mmol), and HATU (129 mg, 0.34 mmol) in Et₃N and DMF (1 mL/3 mL) was stirred for 18 h, and then poured into water (10 mL). The mixture was then extracted with EtOAc (3×). The combined organic extracts were washed with brine (2×), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resultant residue was purified on silica gel, eluting with 5% MeOH/CH₂Cl₂ to give compound 427 (33 mg). MS m/z (M+H⁺) 492.1.

Following the procedure described above for Example 30 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 428 1-[1-({4-[(3-Chlorophenyl)sulfanyl]phenyl}carbonyl)azetidin- 3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 499.1 429 1-[1-({4-[(3-Chlorophenyl)sulfanyl]phenyl}carbonyl)azetidin- 3-yl]-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 499.1 430 1-(Phenylcarbonyl)-4-{1-[(4-{[3- (trifluoromethyl)phenyl]sulfanyl}phenyl)carbonyl]azetidin-3- yl}piperazine MS m/z (M + H⁺) 526.2 431 1-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(4-{[3- (trifluoromethyl)phenyl]sulfanyl}phenyl)carbonyl]azetidin-3- yl}piperazine MS m/z (M + H⁺) 533.1 432 1-(1,3-Thiazol-4-ylcarbonyl)-4-{1-[(4-{[3- (trifluoromethyl)phenyl]sulfanyl}phenyl)carbonyl]azetidin-3- yl}piperazine MS m/z (M + H⁺) 533.1

Example 30a

Following the procedure described above for Example 1c, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Salt Cpd Cpd Name and Data Form 677 1-[1-({4-[(3- N-TFA Chlorophenyl)sulfanyl]phenyl}carbonyl)azetidin-3- yl]-4-(trifluoroacetyl)piperazine MS m/z (M + H⁺) 483.8 790 1-(Trifluoroacetyl)-4-{1-[(4-{[3- N-TFA (trifluoromethyl)phenyl]sulfanyl}phenyl)carbonyl] azetidin-3-yl}piperazine MS m/z (M + H⁺) 517.9

Example 31

A. 4-(3-Chloro-benzensulfonyl)-benzoic acid methyl ester (31a)

To a solution of compound 30c (200 mg, 0.72 mmol) in CH₂Cl₂ (5 mL) was added mCPBA (320 mg, 1.43 mmol) at 0° C. After 2 h, the mixture was poured into 2N KOH solution (20 mL) and extracted with EtOAc (3×). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with 5% EtOAc/hexanes to give compound 31a (138 mg).

B. 4-(3-Chloro-benzensulfonyl)-benzoic acid (31b)

A mixture of compound 31a (138 mg, 0.44 mmol) and LiOH (42 mg, 1.77 mmol) in THF/MeOH/H₂O (2/2/2 mL) was stirred for 4 h. A 15% citric acid solution (10 mL) was added. The mixture was then extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resultant residue, compound 31b (130 mg) was dried under reduced pressure for 18 h and used without further purification.

C. 1-[1-({4-[(3-Chlorophenyl)sulfonyl]phenyl}carbonyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazine, Cpd 433

A mixture of compound 31b (40 mg, 0.14 mmol), compound 2c (49 mg, 0.18 mmol), and HATU (80 mg, 0.20 mmol) in Et₃N (1 mL) and DMF (2 mL) was stirred for 18 h, and was then poured into water (10 mL). The mixture was then extracted with EtOAc (3×). The combined organic extracts were washed with brine (2×), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with 5% MeOH/CH₂Cl₂ to give compound 428 (29 mg). MS m/z (M+H⁺) 524.1.

Following the procedure described above for Example 31, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 508 1-(Phenylcarbonyl)-4-{1-[(4-{[3- (trifluoromethyl)phenyl]sulfonyl}phenyl)carbonyl]azetidin- 3-yl}piperazine MS m/z (M + H⁺) 558.0 876 1-[1-({4-[(3- Chlorophenyl)sulfonyl]phenyl}carbonyl)azetidin-3-yl]-4- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 530.8 651 1-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(4-{[3- (trifluoromethyl)phenyl]sulfonyl}phenyl)carbonyl]azetidin- 3-yl}piperazine MS m/z (M + H⁺) 564.8 1507 1-(1,3-Thiazol-4-ylcarbonyl)-4-{1-[(4-{[3- (trifluoromethyl)benzyl]sulfonyl}phenyl)carbonyl]azetidin- 3-yl}piperazine MS m/z (M + H⁺) 578.8 738 1-(1,3-Thiazol-4-ylcarbonyl)-4-{1-[(4-{[3- (trifluoromethyl)phenyl]sulfonyl}phenyl)carbonyl]azetidin- 3-yl}piperazine MS m/z (M + H⁺) 564.6

Example 31a

Following the procedure described above for Example 31 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Following the procedure described above for Example 31 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 976 1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[4-({[3- (trifluoromethyl)phenyl]sulfonyl}methyl)phenyl]carbonyl}azetidin- 3-yl)piperazine ¹H NMR (CDCl₃): δ 7.80-7.97 (m, 4H), 7.63-7.73 (m, 1H), 7.56 (dd, J = 5.7, 2.4 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 4.34-4.60 (m, 3H), 4.20-4.33 (m, 2H), 4.03-4.20 (m, 2H), 3.86 (br. s., 2H), 3.15-3.32 (m, 1H), 2.37-2.60 (m, 4H), MS m/z (M + H⁺) 578.8 564 1-(Phenylcarbonyl)-4-(1-{[4-({[3- (trifluoromethyl)phenyl]sulfonyl}methyl)phenyl]carbonyl}azetidin- 3-yl)piperazine MS m/z (M + H⁺) 572.0 971 1-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(4-{[3- (trifluoromethyl)benzyl]sulfonyl}phenyl)carbonyl]azetidin- 3-yl}piperazine ¹H NMR (CDCl₃): δ 7.88 (d, J = 3.3 Hz, 1H), 7.65-7.77 (m, 4H), 7.52-7.65 (m, 2H), 7.35-7.52 (m, 2H), 7.24 (s, 1H), 4.39 (s, 4H), 4.17-4.33 (m, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.86 (br. s., 2H), 3.19-3.34 (m, 1H), 2.38-2.59 (m, 4H). MS m/z (M + H⁺) 578.8 977 1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[4-({[3- (trifluoromethyl)phenyl]sulfonyl}methyl)phenyl]carbonyl}azetidin- 3-yl)piperazine MS m/z (M + H⁺) 578.6

Example 31b

D. 10-Oxidophenoxathiine-2-carboxylic acid, 31d

A mixture of phenoxathiine-2-carboxylic acid 31c (0.41 mmol, 100 mg) and sodium perborate tetrahydrate (0.82 mmol, 126 mg) in 3 mL of HOAc was stirred for 6 days at room temperature. TLC indicated 90% conversion to 31d. Water was added and the resulting precipitate was filtered and dried to give 65 mg of 31d, 90% pure.

Following the procedure described above for Example 9 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 807 1-{1-[(10-Oxidophenoxathiin-2-yl)carbonyl]azetidin- 3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 495.1

Example 31c

Following the procedure described above for Example 1c, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compound of the present invention was prepared:

Salt Cpd Cpd Name and Data Form 914 1-[1-({4-[(3-Chlorophenyl)sulfonyl]phenyl}- N-TFA carbonyl)azetidin-3-yl]-4-(trifluoroacetyl)piperazine MS m/z (M + H⁺) 516.8 1493 1-(Trifluoroacetyl)-4-{1-[(4-{[3- N-TFA (trifluoromethyl)phenyl]sulfonyl}phenyl)carbonyl]- azetidin-3-yl}piperazine MS m/z (M + H⁺) 550.5 1498 1-(Trifluoroacetyl)-4-(1-{[4-({[3- N-TFA (trifluoromethyl)phenyl]sulfonyl}methyl)phenyl]- carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 563.8

Example 32

Tert-Butyl (3S)-3-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenoxy]pyrrolidine-1-carboxylate, Cpd 434

To a solution of compound 26d (100 mg, 0.273 mmol) and (R)—N-Boc-3-hydroxyproline in THF was added DIAD at 0° C. The resulting reaction mixture was stirred for 18 h. After dilution with water and extraction with EtOAc (3×), the combined organic extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography on silica gel using 5% MeOH/CH₂Cl₂ to give compound 434 (95 mg). ¹H NMR (CDCl₃): δ 7.52 (d, J=8.6 Hz, 2H), 7.37-7.44 (m, 5H), 7.24-7.29 (m, 3H), 7.18-7.24 (m, 3H), 4.18-4.33 (m, 2H), 4.09-4.17 (m, 3H), 4.01-4.08 (m, 1H), 3.92 (br. S, 1H), 3.74 (br. s., 1H), 3.35-3.63 (m, 2H), 3.17-3.29 (m, 1H), 2.20-2.50 (m, 4H); MS m/z (M+H⁺) 506.0.

Following the procedure described above for Example 32 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 435 1-(1-{[4-(Cyclohexyloxy)phenyl]carbonyl}azetidin-3-yl)- 4-(phenylcarbonyl)piperazine ¹H NMR (CDCl₃): δ 7.58 (d, J = 8.8 Hz, 2H), 7.36-7.44 (m, 5H), 6.88 (d, J = 8.8 Hz, 2H), 4.26-4.38 (m, 2H), 4.25-4.12 (m, 2H), 4.07 (br. s, 1H), 3.82-3.99 (m, 1H), 3.48 (br. s., 2H), 3.15-3.26 (m, 1H), 2.17-2.54 (m, 4H), 1.93-2.03 (m, 1H), 1.75-1.89 (m, 2H), 1.46-1.63 (m, 2H), 1.31-1.46 (m, 3H), 1.21-1.31 (m, 2H). MS m/z (M + H⁺) 448.0 436 1-(1-{[4-(Cyclopentyloxy)phenyl]carbonyl}azetidin-3-yl)- 4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 434.2 437 tert-Butyl 4-[4-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)phenoxy]piperidine-1- carboxylate MS m/z (M + H⁺) 549.3 438 tert-Butyl (3R)-3-[4-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)phenoxy]pyrrolidine-1- carboxylate MS m/z (M + H⁺) 535.3

Example 33

A. (3S)-3-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenoxy]pyrrolidine, 33a

To a solution of compound 434 (87.7 mg, 0.164 mmol) in CH₂Cl₂ (1 mL) was added TFA (0.5 mL). The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure to give compound 33a, which was used without further purification.

B. (3S)—N,N-Dimethyl-3-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenoxy]pyrrolidine-1-sulfonamide, Cpd 439

A solution of compound 33a (0.164 mmol) and Et₃N (0.5 mL) in CH₂Cl₂ (2 mL) was treated with N,N-dimethylsulfamoyl chloride (26 uL, 0.246 mmol) at room temperature. The resulting mixture was stirred for 3 h, and the solvent was then removed under reduced pressure. The resultant residue was directly loaded onto a silica gel column and was purified by silica gel flash column chromatography, eluting with 5% MeOH/CH₂Cl₂ to give compound 439 (51.5 mg). ¹H NMR (CDCl₃): δ 7.61 (d, J=8.21 Hz, 2H), 7.36-7.46 (m, 5H), 6.86 (d, J=8.6 Hz, 2H), 4.98 (m, 1H), 4.31 (br. s., 1H), 4.11-4.26 (m, 2H), 4.05 (br. s., 1H), 3.87-3.96 (m, 1H), 3.84 (m, 1H), 3.70-3.79 (m, 1H), 3.66 (dd, J=11.4, 4.8 Hz, 1H), 3.39-3.58 (m, 4H), 3.21-3.26 (m, 1H), 2.82 (s, 6H), 2.42 (br. s., 4H), 2.19-2.29 (m, 2H); MS m/z (M+H⁺) 542.0.

Following the procedure described above for Example 33 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 440 1-(Phenylcarbonyl)-4-{1-[(4-{[1-(phenylcarbonyl)piperidin-4- yl]oxy}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 553.3 441 1-[1-({4-[(1-Acetylpiperidin-4- yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 491.3 442 1-(Phenylcarbonyl)-4-{1-[(4-{[(3S)-1- (phenylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)carbonyl]azetidin- 3-yl}piperazine MS m/z (M + H⁺) 539.3 443 1-{1-[(4-{[(3R)-1-(Cyclohexylcarbonyl)pyrrolidin-3- yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 545.3 444 1-(Phenylcarbonyl)-4-{1-[(4-{[(3R)-1- (phenylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)carbonyl]azetidin- 3-yl}piperazine MS m/z (M + H⁺) 539.3 445 1-{1-[(4-{[(3R)-1-(2,2-Dimethylpropanoyl)pyrrolidin-3- yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 519.3 446 (3S)—N,N-Dimethyl-3-[4-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)phenoxy]pyrrolidine-1-carboxamide MS m/z (M + H⁺) 506.3 447 1-(Phenylcarbonyl)-4-{1-[(4-{[(3S)-1-(pyrrolidin-1- ylsulfonyl)pyrrolidin-3-yl]oxy}phenyl)carbonyl]azetidin-3- yl}piperazine MS m/z (M + H⁺) 568.3 448 1-(Phenylcarbonyl)-4-{1-[(4-{[(3S)-1-(pyrrolidin-1- ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)carbonyl]azetidin-3- yl}piperazine MS m/z (M + H⁺) 532.3 449 4-({(3S)-3-[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)phenoxy]pyrrolidin-1-yl}carbonyl)morpholine MS m/z (M + H⁺) 548.3

Example 34

A. Tert-Butyl 3-(2-iodo-4-methoxycarbonyl-phenoxy)-pyrrolidine-1-carboxylate, 34b

To a solution of compound 34a (500 mg, 1.8 mmol), compound 32a (504 mg, 2.7 mmol) and PPh₃ (707 mg, 2.7 mmol) in THF (10 mL) was added DIAD (0.52 mL, 2.7 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 1 h, then warmed up to room temperature and stirred for 18 h. The mixture was poured into water and extracted with EtOAc (3×). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with 50% EtOAc/hexanes to give compound 34b (704 mg).

B. Methyl 3-iodo-4-[1-(pyrrolidine-1-carbonyl)-pyrrolidin-3-yloxy]-benzoate, 34d

To a solution of compound 34b (210 mg, 0.47 mmol) in CH₂Cl₂ (3 mL) was added TFA (1.5 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure. The resultant residue was dried under reduced pressure for 2 h. To the residue was added CH₂Cl₂ (3 mL) and Et₃N (1 mL), followed by the addition of compound 34c (77 μL, 0.7 mmol). The resulting mixture was stirred for 2 h, then poured into water (50 mL) and extracted with EtOAc (3×). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with 80% EtOAc/hexanes to give compound 34d (180 mg).

C. 3-Iodo-4-[1-(pyrrolidine-1-carbonyl)-pyrrolidin-3-yloxy]-benzoic acid, 34e

A mixture of compound 34d (180 mg, 0.41 mmol), LiOH (39 mg, 1.62 mmol), THF (3 mL), MeOH (3 mL), and H₂O (3 mL) was stirred at room temperature for 4 h. The mixture was acidified with 15% aqueous citric acid and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resultant residue was dried under reduced pressure for 2 h to give compound 34e (166 mg).

D. 3-Iodo-4-[1-(pyrrolidine-1-carbonyl)-pyrrolidin-3-yloxy]-benzoyl chloride, 34f

To a solution of compound 34e (166 mg, 0.39 mmol) in THF (4 mL) was added oxalyl dichloride (43 μL, 0.50 mmol) dropwise at 0° C., followed by the addition of 2 drops of DMF. The resulting mixture was stirred at 0° C. for 3 h, warmed to room temperature, and stirred for 18 h. The solvents were removed under reduced pressure. The resultant residue, compound 34f, was dried under reduced pressure for 2 h and used in the following step without further purification.

E. 1-{1-[(3-Iodo-4-{[(3S)-1-(pyrrolidin-1-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine, Cpd 450

To a mixture of compound 2c (61 mg, 0.25 mmol), Et₃N (0.5 mL), and CH₂Cl₂ (2.5 mL) was added a solution of compound 34f in CH₂Cl₂ (1 mL). The resulting mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in CH₂Cl₂ (1 mL), directly loaded onto a silica gel column, and purified by flash column chromatography, eluting with 5% MeOH/CH₂Cl₂ to give compound 451 (56 mg). ¹H NMR (CDCl₃): δ 8.06 (d, J=2.3 Hz, 1H), 7.60 (dd, J=8.5, 2.1 Hz, 1H), 7.34-7.48 (m, 5H), 6.80 (d, J=8.6 Hz, 1H), 5.01 (br. s., 1H), 3.66-4.36 (m, 8H), 3.28-3.64 (m, 8H), 3.12-3.27 (m, 1H), 2.05-2.56 (m, 6H), 1.55-1.97 (m, 4H).

Following the procedure described above for Example 34 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 451 (3S)-3-[2-Iodo-4-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)phenoxy]-N,N-dimethylpyrrolidine- 1-carboxamide MS m/z (M + H⁺) 632.2 452 1-{1-[(3-Iodo-4-{[(3S)-1-(pyrrolidin-1-ylcarbonyl)pyrrolidin- 3-yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 665.2

Example 35

A. Methyl 4-[(3-Chlorophenoxy)methyl]benzoate, 35c

To a mixture of compound 35a (300 mg, 1.31 mmol) and K₂CO₃ (400 mg, 2.88 mmol) in DMF (1 mL) was added compound 35b (251 mg, 2.0 mmol). The resulting mixture was stirred at room temperature for 6 h. The mixture was poured into water (50 mL) and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over NaSO₄, filtered, and concentrated under reduced pressure. The resultant residue was purified by silica gel flash column chromatography, eluting with 20% EtOAc/hexanes to yield compound 35c (340 mg).

B. 4-[(3-Chlorophenoxy)methyl]benzoic acid, 35d

A mixture of compound 35c (340 mg, 1.18 mmol) and LiOH (114 mg, 4.74 mmol) in THF/MeOH/H₂O (3/3/3 mL) was stirred for 4 h. A 15% citric acid solution (10 mL) was added. The mixture was then extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The resultant residue, compound 35d (230 mg) was dried under reduced pressure for 18 h and used without further purification.

C. 1-[1-({4-[(3-Chlorophenoxy)methyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 453

A mixture of compound 35d (77 mg, 0.29 mmol), compound 5e (108 mg, 0.38 mmol) and HATU (165 mg, 0.44 mmol) in Et₃N (1 mL) and DMF (3 mL) was stirred for 18 h, and then poured into water (10 mL). The mixture was then extracted with EtOAc (3×). The combined organic extracts were washed with brine (2×), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography, eluting with 5% MeOH/CH₂Cl₂, to give compound 453 (67 mg). MS m/z (M+H⁺) 497.1. ¹H NMR (CD₃OD): δ 7.95 (d, J=2.0 Hz, 1H), 7.8 (d, J=2.0 Hz, 1H), 7.65 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H), 7.25 (t, J=8.0 Hz, 1H), 7.02 (s, 1H), 6.90-6.98 (m, 2H), 5.15 (s, 2H), 4.32-4.45 (m, 2H), 4.15-4.25 (m, 2H), 4.00-4.10 (m, 1H), 3.70-3.82 (br. s, 2H), 2.47 (br. s., 4H).

Following the procedure described above for Example 35 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 454 1-{1-[(4-{[(3- Chlorophenyl)sulfanyl]methyl}phenyl)carbonyl]azetidin-3- yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 513.1 455 3-Chloro-N-[4-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)benzyl]aniline MS m/z (M + H⁺) 496.1 548 1-[1-({4-[(3- Chlorophenoxy)methyl]phenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 490.0 959 1-[1-({4-[(3- Chlorophenoxy)methyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3- thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 497.0

Example 35a

Following the procedure described above for Example 35 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Following the procedure described above for Example 35 or Example 1, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 551 1-{1-[(4-{[(3- Chlorophenyl)sulfanyl]methyl}phenyl)carbonyl]azetidin- 3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 506.0 549 3-Chloro-N-[4-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)benzyl]aniline MS m/z (M + H⁺) 489.0 956 1-{1-[(4-{[(3- Chlorophenyl)sulfanyl]methyl}phenyl)carbonyl]azetidin- 3-yl}-4-(1,3-thiazol-4-ylcarbonyl) piperazine MS m/z (M + H⁺) 513.0 969 3-Chloro-N-[4-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)benzyl]aniline MS m/z (M + H⁺) 496.0

Example 35b

Following the procedure described above for Example 1c, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Salt Cpd Cpd Name and Data Form 955 1-{1-[(4-{[(3- N-TFA Chlorophenyl)sulfanyl]methyl}phenyl)carbonyl]azetidin- 3-yl}-4-(trifluoroacetyl)piperazine MS m/z (M + H⁺) 498.0 964 3-Chloro-N-[4-({3-[4-(trifluoroacetyl)piperazin-1- N-TFA yl]azetidin-1-yl}carbonyl)benzyl]aniline MS m/z (M + H⁺) 481.0

Example 36

1-(Phenylcarbonyl)-4-{1-[(2-pyrrolidin-3-ylphenyl)carbonyl]azetidin-3-yl}piperazine, Cpd 456

To a solution of compound III (300 mg, 0.58 mmol) in 1,4-dioxane (10 mL) was added 6N HCl (3 mL). After stirring for 4 h, the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and 3N NaOH, and the organic phase was isolated and dried over MgSO₄. The mixture was filtered, the filtrate concentrated under reduced pressure, and the residue was purified by reverse phase HPLC to give compound 456 (52.3 mg). LC/MS m/z (M+H⁺) 419.36 (calculated for C₂₅H₃₀N₄O₄, 418.54).

Example 37

A. Tert-Butyl 4-[1-(diphenylmethyl)azetidin-3-yl]-3-(hydroxymethyl)piperazine-1-carboxylate, 37b

Compound 37a (811 mg, 3.21 mmol) was added in one portion to a stirring suspension of anhydrous K₂CO₃ (1.07 g, 7.9 mmol) in MeOH (4 mL). The mixture was stirred for 1.5 h at room temperature, and the MeOH was then removed under reduced pressure to near-dryness. The resulting white slurry was triturated with CH₂Cl₂ (40 mL) and filtered through a medium-porosity glass fitted funnel. The solids were washed with additional CH₂Cl₂ and the combined filtrates were concentrated and dried under reduced pressure to give compound 37a (733 mg) as a white solid, the free base of the HCl salt of 37a.

The material was suspended in CH₃CN (8 mL) with compound 1e (1.07 g, 3.37 mmol). Diisopropylethylamine (1.23 mL, 7.06 mmol) was added and the mixture was heated at 60° C. for 14 h. EtOAc (100 mL) was added and the organic phase was washed with water (20 mL) and brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a crude residue (1.42 g) as a pale orange foam. The material was purified by medium pressure liquid chromatography (MPLC) using an ISCO CombiFlash system (silica gel, 10-50% EtOAc/hexanes) to give compound 37b (979 mg) as a white foam. ¹H NMR (400 MHz, CDCl₃): δ 7.39 (d, J=8.1 Hz, 4H), 7.23-7.33 (m, 4H), 7.14-7.23 (m, 2H), 4.34 (s, 1H), 3.28-3.58 (m, 8H), 2.76-2.95 (m, 2H), 2.26-2.75 (m, 4H), 2.20 (dt, J=12.3, 4.9 Hz, 1H), 1.44 (s, 9H); LCMS m/z (M+H⁺) 438.5, (M+Na⁺) 460.5.

B. {1-[1-(Diphenylmethyl)azetidin-3-yl]-piperazin-2-yl}methanol, 37c

Compound 37b (450 mg, 1.03 mmol) was dissolved in CH₂Cl₂ (6 mL) and TFA (3 mL) and was stirred at 20° C. for 2.5 h. The reaction mixture was concentrated to dryness under reduced pressure to give the TFA salt of compound 37c as an orange foam. Compound 37c was used in the following step without further purification. MS m/z (M+H⁺) 338.2.

C. {1-[1-(Diphenylmethyl)azetidin-3-yl]-4-(phenylcarbonyl)piperazin-2-yl}methanol, 37e

Compound 37c (1.03 mmol) was dissolved in CH₂Cl₂ (5 mL) and cooled in an ice water bath to 0° C. A 10% aqueous Na₂CO₃ solution (5 mL) was added and a solution of compound 37d (143 μL, 1.23 mmol) dissolved in CH₂Cl₂ (1 mL) was added dropwise. The resultant mixture was allowed to warm to 20° C. and then stirred rapidly for 62 h. CH₂Cl₂ (10 mL) was added to the reaction mixture and the aqueous phase was extracted with CH₂Cl₂ (2×20 mL). The combined organic extracts were washed with brine, dried over Na₂SO₄, filtered, and concentrated to give compound 37e (465 mg) as an off white foam. Compound 37e was used in the following step without further purification. ¹H NMR (400 MHz, CDCl₃): δ 7.39 (m, 9H), 7.22-7.32 (m, 4H), 7.14-7.23 (m, 2H), 4.35 (s, 1H), 4.07 (br. s, 1H), 3.30-3.71 (complex, 8H), 2.2-3.0 (complex, 6H); LCMS m/z (M+H⁺) 442.2.

D. [1-Azetidin-3-yl-4-(phenylcarbonyl)piperazin-2-yl]methanol, 37f

Compound 37e (450 mg, 1.02 mmol) was added to a 500 mL-Parr hydrogenation bottle and dissolved in absolute EtOH (6 mL). A 12N conc. HCl solution (95 μL, 1.14 mmol) was added and the bottle was purged with N₂. 10% Pd/C (264 mg) was added and the mixture was shaken under 60 psi of H₂ for 14 h. An additional amount of 10% Pd/C (430 mg) was added and the mixture was returned to 60 psi of H₂ and shaken 5 h more. The mixture was filtered through a pad of diatomaceous earth, and the solids were rinsed thoroughly with MeOH. The fitrate was concentrated to dryness under reduced pressure to afford crude compound 37f as a sticky oil (428 mg) which was used in the following step without further purification. LC/MS m/z (M+H⁺) 276.3.

E. [1-{1-[(4-Benzylphenyl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazin-2-yl]ethanol, Cpd 457

Compound 3a (142 mg, 0.67 mmol) and HATU (256 mg, 0.67 mmol) were suspended in CH₂Cl₂ (1 mL) and DMF (0.2 mL). Et₃N (195 μL, 1.4 mmol) was added and the solution was stirred for 15 min at 20° C. Crude compound 37f (214 mg, approximately 0.56 mmol) was dissolved in 1:1 CH₂Cl₂/DMF (3 mL) and was added in portions to the solution of compound 3a and the mixture was stirred for 64 h. The organic solution was diluted with EtOAc (50 mL), and washed sequentially with water (3×10 mL), and brine (10 mL). The organic phase was dried over Na₂SO₄, filtered, and the filtrate concentrated under reduced pressure to give a yellow oil (310 mg). The crude oil was purified by MPLC (4 g Silicycle SiO₂ cartridge, 15-80% acetone/hexanes) to give compound 457 as a white foam (104 mg). ¹H NMR (400 MHz, CDCl₃) δ: 7.53 (d, J=7.8 Hz, 2H), 7.42 (br. s, 5H), 7.11-7.37 (m, 7H), 4.26 (m, 5H), 4.00 (s, 2H), 3.71-3.89 (m, 1H), 3.54-3.71 (m, 3H), 3.25-3.54 (m, 3H), 2.92 (br. s., 1H), 2.64 (br. s., 1H), 2.41 (br. s., 1H); LCMS m/z (M+H⁺) 470.5.

Following the procedure described above for Example 37 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 458 {1-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazin-2-yl}methanol ¹H NMR (400 MHz, CDCl₃): δ 7.65-7.73 (m, 2H), 7.61 (dd, J = 11.6, 8.1 Hz, 4H), 7.33-7.50 (m, 10H), 3.96-4.49 (m, 5H), 3.76-3.91 (m, 1H), 3.63 (m, 3H), 3.32-3.53 (m, 1H), 2.95 (br. s., 1H), 2.64 (br. s., 1H), 2.45 (br. s., 1H) LCMS m/z (M + H⁺) 456.5 459 [4-{1-[(4-Benzylphenyl)carbonyl]azetidin-3-yl}-1- (phenylcarbonyl)piperazin-2-yl]methanol ¹H NMR (400 MHz, CDCl₃): δ 7.55 (d, J = 8.1 Hz, 2H), 7.35-7.46 (m, 5H), 7.10-7.34 (m, 7H), 4.82 (br. s., 1H), 4.01 (s, 2H), 3.72-4.40 (m, 5H), 3.52 (br. s., 1H), 3.16 (br. s., 1H), 2.54-3.04 (m, 2H), 1.93-2.30 (m, 4H) LCMS m/z (M + H⁺) 470.5 460 {4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-1- (phenylcarbonyl)piperazin-2-yl}methanol ¹H NMR (400 MHz, CDCl₃): δ 7.67-7.75 (d, J = 8.3 Hz, 2H), 7.55-7.67 (m, 4H), 7.34-7.52 (m, 8H), 3.39-4.96 (m, 9H), 3.20 (quin, 1H), 2.51-3.05 (m, 3H), 2.22 (br. s., 1H), 2.04 (br. s., 1H) LCMS m/z (M + H⁺) 456.5

Example 38

4,4,4-Trifluoro-N-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)phenyl]butanamide, Cpd 497

A mixture of Cpd 495 (65 mg, prepared according to Example 9), 4,4,4-trifluorobutanoic acid (30 mg), HATU (116 mg), and TEA (0.12 mL) in DCM 1.5 mL) was stirred at room temperature for 5 hr. The reaction mixture was diluted with DCM and water. The normal work-up followed by chromatography gave Cpd 497 (71 mg). MS m/z (M+H⁺) 489.5.

Following the procedure described above for Example 38 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 498 2-Phenyl-N-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)phenyl]acetamide MS m/z (M + H⁺) 483.6 499 N-[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenyl]cyclohexanecarboxamide MS m/z (M + H⁺) 475.6 500 2-Ethyl-N-[4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)phenyl]butanamide MS m/z (M + H⁺) 463.6⁺ 501 N-[4-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)phenyl]benzamide MSm/z (M + H⁺) 469.2

Example 39

A. N-(Naphthalen-2-ylmethyl)-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline, Cpd 495

Cpd 496 was dissolved in CH₂Cl₂ and TFA and was stirred at 20° C. The reaction mixture was concentrated to dryness under reduced pressure to give Cpd 495, which was used in the following step without further purification. MS m/z (M+H⁺) 365.

B. N-(Naphthalen-2-ylmethyl)-4-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline, Cpd 491

A mixture of Cpd 495 (100 mg, 0.27 mmol), compound 39a (75 mg, 0.48 mmol) and AcOH (0.5 mL) in 1,2 dichloroethane (3 mL) was stirred for 1 h, then NaBH(OAc)₃ (136 mg, 0.64 mmol) was added. The resulting mixture was stirred overnight, then was poured into 2N aqueous KOH solution (20 mL) and extracted with EtOAc. The combined extracts were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with 5% MeOH/CH₂Cl₂ to give 33.2 mg of Cpd 491. ¹H NMR (400 MHz, CDCl₃): δ 7.75-7.85 (m, 4H), 7.43-7.53 (m, 5H), 7.35-7.42 (m, 5H), 6.61 (d, J=8.8 Hz, 2H), 4.64 (br. s., 1H), 4.51 (s, 2H), 4.27 (br. s., 1H), 4.08-4.35 (m, 3H), 4.02 (s, 1H), 3.89 (s, 1H), 3.71 (br. s., 1H), 3.34-3.55 (m, 2H), 3.10-3.22 (m, 1H), 2.13-2.49 (m, 3H); MS m/z (M+H⁺) 505.3.

Following the procedure described above for Example 39 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 492 N-(2-Chlorobenzyl)-4-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)aniline MS (m/z) (M + H⁺) 489.2 493 N-(3,4-Dichlorobenzyl)-4-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)aniline MS (m/z) (M + H⁺) 523.2 494 N-[4-Fluoro-3-(trifluoromethyl)benzyl]-4-({3-[4- (phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)aniline MS (m/z) (M + H⁺) 541.2

Example 40

1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[(1RS,2RS)-2-{4-[(trifluoromethyl)sulfanyl]phenyl}cyclopropyl]carbonyl}azetidin-3-yl)piperazine, Cpd 645 (racemic, trans)

Trimethylsulfoxonium iodide 40a (1.15 mmol, 253 mg) and sodium hydride (60% dispersion in mineral oil, 1.1 mmol, 44 mg) were combined in 3 mL of dry DMSO and stirred 20 min at room temperature. Cpd 648, prepared in Example 5, was added and the mixture was stirred 15 min at room temperature, then heated at 50° C. overnight. After cooling, the mixture was partitioned between EtOAc and water, The organic layer was separated and concentrated to give crude product that was purified by preparative reverse-phase chromatography to afford 9.1 mg (2%) of Cpd 645 as the mono-TFA salt. MS m/z (M+H⁺) 497.2.

Following the procedure described above for Example 40, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compound of the present invention was prepared:

Cpd Cpd Name and Data 642 1-(1-{[(1RS,2RS)-2-(2- Chlorophenyl)cyclopropyl]carbonyl}azetidin-3-yl)- 4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 431.1

Example 41

Intentionally left blank.

Example 42

A. Methyl 4-(4-(trifluoromethyl)benzyl)benzoate, 42b

Argon was bubbled through a mixture of methyl 4-bromobenzoate 42a (9.3 mmol, 2.0 g), 2 mL of THF, and 4-trifluoromethylbenzylzinc chloride (0.5 M in THF, 46.5 mmol, 93 mL) for 5 min Pd(dffp)Cl₂.CH₂Cl₂(0.5 mol, 409 mg) was added and the reaction tube was capped and heated at 70° C. for 16 h. The mixture was cooled and filtered through Celite. Water was added to the filtrate and the resulting solid was filtered off. The organic solution was dried over MgSO₄ and concentrated. The crude product was purified by flash chromatography (silica gel, 0-10% EtOAc in heptane) to give 1.5 g (55%) of methyl 4-(4-(trifluoromethyl)benzyl)benzoate, 42b.

B. 4-(4-(Trifluoromethyl)benzyl)benzoic acid, 42c

Following the procedure described in Example 9i, Step P, methyl 4-(4-(trifluoromethyl)benzyl)benzoate 42b (1.5 g, 5.1 mmol) was converted to methyl 1.31 g (92%) of 4-(4-(trifluoromethyl)benzyl)benzoic acid, 42c. MS m/z (M+H⁺) 279.1.

Following the procedure described above for Example 42 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Intermediate compounds were optionally prepared by an alternative procedure:

C. Methyl 4-(4-(trifluoromethyl)benzyl)benzoate, 42b

A mixture of 4-bromomethyl-benzoic acid methyl ester 42d (1.0 g, 4.37 mmol), 4-trifluorophenyl boronic acid 42e (0.995 g, 5.24 mmol), and Pd(PPh₃)₄ (50 mg, 0.044 mmol) in dioxane (15 mL) was stirred at room temperature for 1 min. Next, 4 mL of 2 M aqueous Na₂CO₃ solution was added. The resulting solution was heated at 90° C. for 5 h and was then cooled to rt. EtOAc and water were added to the reaction mixture. The organics were concentrated and purified by flash chromatography (silica gel, 5% EtOAc/hexanes) to give methyl 4-(4-(trifluoromethyl)benzyl)benzoate, 42b.

Following the procedure described above for Example 2 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 96 1-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]-4-({4-[4- (trifluoromethyl)benzyl]phenyl}carbonyl)piperazine ¹H NMR (400 MHz, CDCl₃): δ 9.23 (s, 1H); 8.44 (s, 1H); 8.0-7.8 (m, 2H); 7.76-7.63 (m, 2H); 7.5 (d, 1H); 7.44-7.32 (m, 3H); 4.9-4.7 (m, 3H); 4.3-4.2 (m, 2H); 4.19-4.04 (m, 3H) MS m/z (M + H⁺) 515.1 97 1-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]-4-({4-[4- (trifluoromethyl)benzyl]phenyl}carbonyl)piperazine ¹H NMR (400 MHz, CDCl₃): δ 8.12 (m, 2H); 7.68 (m, 2H); 7.5 (m, 2H); 7.4 (m, 4H); 4.85 (bs, 2H); 4.47-4.26 (bm, 3H); 3.52 (bs, 4H); 3.02 (bs, 2H). MS m/z (M + H⁺) 495.1 006 1-({4-Fluoro-3-[4- (trifluoromethyl)benzyl]phenyl}carbonyl)-4-[1-(1,3-thiazol- 2-ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 533.1 016 1-({2-Methyl-3-[4- (trifluoromethyl)benzyl]phenyl}carbonyl)-4-[1-(1,3-thiazol- 5-ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 529.2

Following the procedure described above for Example 9 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 563 1-[1-({4-Fluoro-3-[4- (trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-yl]- 4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 526.1 1007 1-[1-({4-Fluoro-3-[4- (trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-yl]- 4-(1,3-thiazol-2-ylcarbonyl)piperazine ¹H NMR (400 MHz, CDCl₃): δ 7.89 (s, 1H); 7.78 (s, 1H); 7.50 (m, 5H); 7.82 (m, 2H); 7.12 (t, 1H); 4.69 (bm, 2H); 4.48 (bm, 2H); 4.32 (bm, 2H); 4.0 (s, bm, 5H); 3.5 (bm, s 2H) MS m/z (M + H⁺) 533.1 1008 1-[1-({2-Methyl-3-[4- (trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-yl]- 4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 529.2 1009 1-[1-({2-Methyl-3-[4- (trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-yl]- 4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 529.2 1013 1-[1-({2-Methyl-3-[4- (trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-yl]- 4-(1H-pyrrol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 511.2 1014 1-(Isothiazol-5-ylcarbonyl)-4-[1-({2-methyl-3-[4- (trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3- yl]piperazine MS m/z (M + H⁺) 529.2 1015 1-[1-({2-Methyl-3-[4- (trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3-yl]- 4-(1,3-thiazol-5-ylcarbonyl)piperazine MS m/z (M + H⁺) 529.2 995 1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[3- (trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3- yl]piperazine MS m/z 515 (M + H⁺) 985 1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[4- (trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3- yl]piperazine MS m/z (M + H⁺) 515 998 1-(1,3-Thiazol-4-ylcarbonyl)-4-[1-({4-[3- (trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3- yl]piperazine MS m/z (M + H⁺) 515 999 1-(1,3-Thiazol-4-ylcarbonyl)-4-[1-({4-[4- (trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3- yl]piperazine MS m/z (M + H⁺) 515 771 1-(Phenylcarbonyl)-4-[1-({4-[4- (trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3- yl]piperazine MS m/z (M + H⁺) 508 547 1-(Phenylcarbonyl)-4-[1-({4-[3- (trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3- yl]piperazine MS m/z (M + H⁺) 508

Example 43

A. Methyl 3-(4-fluorobenzoyl)-1H-indole-6-carboxylate, 43c

A solution of 4-fluorobenzoyl chloride 43b (2 mmol, 0.24 mL) in 8 mL of DCE was added dropwise to an ice-cold solution of methyl 1H-indole-6-carboxylate 43a (1.43 mmol, 250 mg) and diethylaluminum chloride (1 M in hexanes, 1.86 mmol, 1.86 mL) in 8 mL of DCE. After 2 h at 0° C., the mixture was warmed to room temperature and was stirred overnight. To the mixture was added pH 7 buffer; the resulting solid was filtered and washed with CH₂Cl₂ to give 162 mg (38%) of methyl 3-(4-fluorobenzoyl)-1H-indole-6-carboxylate 43c. MS m/z (M+H⁺) 298.0.

B. 3-(4-Fluorobenzoyl)-1H-indole-6-carboxylic acid, 43d

Following the procedure described in Example 9i, Step P, 110 mg (72%) of 3-(4-fluorobenzoyl)-1H-indole-6-carboxylic acid was obtained.

Following the procedure described above for Example 43 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Following the procedure described above for Example 9 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1025 (4-Fluorophenyl)[6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indol-3-yl]methanone MS m/z (M + H⁺) 518.2 802 ((4,4-Difluorocyclohexyl)[6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indol-3-yl]methanone MS m/z (M + H⁺) 542.1 949 (6-Chloropyridin-3-yl)[6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indol-3-yl]methanone MS m/z (M + H⁺) 535.0 950 Pyridin-3-yl[6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin- 1-yl]azetidin-1-yl}carbonyl)-1H-indol-3-yl]methanone MS m/z (M + H⁺) 501.0

Example 44

A. Methyl 4-(pyridin-2-yloxy)-benzoate, 44b

A mixture of 29a (433 mg, 2.85 mmol), 44a (300 mg, 1.90 mmol), Cu(biPy)₂BF₄ (88 mg, 0.19 mmol), K₃PO₄ (805 mg, 3.80 mmol), and DMF (1.5 mL) was heated at 140° C. for 1 h. After 0.5 h, the mixture was poured into water (60 mL) and extracted with EtOAc. The combined extracts were washed with brine, dried over Na₂SO₄ and concentrated. The crude product was purified by flash column chromatography (silica gel, 20% EtOAc/hexanes) to give 298 mg of 44b.

B. 4-(Pyridin-2-yloxy)-benzoic acid, 44c

A mixture of 44b (430 mg, 1.87 mmol), LiOH (180 mg, 7.5 mmol), THF (3 mL), MeOH (3 mL), and H₂O (3 mL) was stirred at room temperature for 4 h. Then the reaction mixture was acidified with 15% citric acid (10 mL). The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated to give 44c (350 mg).

C. 1-(1-{[4-(Pyridin-2-yloxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 913

A mixture of 44c (60 mg, 0.28 mmol), 5e (105 mg, 0.36 mmol), HATU (159 mg, 0.42 mmol), Et₃N (1 mL), and DMF (3 mL) was stirred at room temperature overnight, and then poured into water (10 mL). The mixture was extracted with EtOAc. The extracts were washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by flash column chromatography (silica gel, 7% MeOH/CH₂Cl₂) to give 98 mg of Cpd 913. MS m/z (M+H⁺) 450.0.

Following the procedure described above for Example 44, Steps A and B, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared.

Following the procedure described above for Example 44, Step C, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared.

Cpd Cpd Name and Data 527 1-(Phenylcarbonyl)-4-(1-{[4-(pyridin-3- yloxy)phenyl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 443.0 507 1-{1-[(4-{[3-Chloro-5-(trifluoromethyl)pyridin-2- yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 545.0 533 1-[1-({4-[(5-Methoxypyridin-3- yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 497.0 1484 1-(Phenylcarbonyl)-4-(1-{[4-(pyridin-2- yloxy)phenyl]carbonyl}azetidin-3-yl)piperazine MS m/z (M + H⁺) 443.0 875 1-(1-{[4-(3-Chlorophenoxy)-3- fluorophenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 500.8 663 1-{1-[(4-{[3-Chloro-5-(trifluoromethyl)pyridin-2- yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 551.8 734 1-(1-{[4-(Pyridin-3-yloxy)phenyl]carbonyl}azetidin-3-yl)- 4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 450.0 904 1-[1-({4-[(5-Methoxypyridin-3- yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 480.0 532 1-[1-({4-[(5-Bromopyridin-2- yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 522.8 537 1-(1-{[3-Fluoro-4-(pyridin-2- yloxy)phenyl]carbonyl}azetidin-3-yl)-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 461.0 520 1-[1-({4-[(5-Chloropyridin-2- yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 477.0 525 1-(1-{[3-Chloro-4-(pyridin-2- yloxy)phenyl]carbonyl}azetidin-3-yl)-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 477.0 522 1-[1-({4-[(6-Fluoropyridin-2- yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 504.0 518 1-(Phenylcarbonyl)-4-{1-[(4-{[4-(trifluoromethyl)pyridin- 2-yl]oxy}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 511.0 877 1-[1-({4-[(5-Bromopyridin-2- yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 529.8 765 1-[1-({4-[(5-Bromopyridin-2- yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 529.8 909 1-(1-{[3-Fluoro-4-(pyridin-2- yloxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 468.0 717 1-[1-({4-[(5-Chloropyridin-2- yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 484.0 752 1-(1-{[3-Chloro-4-(pyridin-2- yloxy)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 484.0 715 1-[1-({4-[(6-Fluoropyridin-2- yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 468.0 652 1-(1,3-Thiazol-2-ylcarbonyl)-4-{1-[(4-{[4- (trifluoromethyl)pyridin-2- yl]oxy}phenyl)carbonyl]azetidin-3-yl}piperazine MS m/z (M + H⁺) 518.0

Example 44a

Following the procedure described above for Example 1c, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data Salt Form 837 1-(Trifluoroacetyl)-4-{1-[(4-{[4- N-TFA (trifluoromethyl)pyridin-2- yl]oxy}phenyl)carbonyl]azetidin-3- yl}piperazine MS m/z (M + H⁺) 503.0 869 1-(1-{[4-(Pyridin-2- N-TFA yloxy)phenyl]carbonyl}azetidin-3-yl)-4- (trifluoroacetyl)piperazine MS m/z (M + H⁺) 435.0 872 1-[1-({4-[(5-Bromopyridin-2- N-TFA yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4- (trifluoroacetyl)piperazine MS m/z (M + H⁺) 512.8 802 1-{1-[(4-{[3-Chloro-5- N-TFA (trifluoromethyl)pyridin-2- yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4- (trifluoroacetyl)piperazine MS m/z (M + H⁺) 536.8

Example 44b

Following the procedure described above for Example 1, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared.

Cpd Cpd Name and Data 922 1-(1-{[4-(Pyridin-2-yloxy)phenyl]carbonyl}azetidin-3-yl)-4- (1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 450.0 757 1-[1-({4-[(5-Chloropyridin-2- yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 484.0 784 1-[1-({4-[(6-Fluoropyridin-2- yl)oxy]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 468.0 769 1-(1,3-Thiazol-4-ylcarbonyl)-4-{1-[(4-{[4- (trifluoromethyl)pyridin-2-yl]oxy}phenyl)carbonyl]azetidin- 3-yl}piperazine MS m/z (M + H⁺) 518.0 720 1-{1-[(4-{[3-Chloro-5-(trifluoromethyl)pyridin-2- yl]oxy}phenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 551.8

Example 45

A. Methyl 6-(3-chloro-phenoxy)-nicotinate, 5c

A mixture of 45a (200 mg, 0.926 mmol), 45b (178 mg, 1.39 mmol), Cu(biPy)₂BF₄ (43 mg, 0.09 mmol), K₃PO₄ (392 mg, 1.85 mmol), and DMF (1.0 mL) was heated at 140° C. for 1 h. The reaction mixture was then poured into water (30 mL) and extracted with EtOAc. The extracts were washed with brine, dried over Na₂SO₄, and concentrated. The crude product was purified by flash column chromatography (silica gel, 20% EtOAc/hexanes) to give 202 mg of 45c.

B. 6-(3-Chloro-phenoxy)-nicotinic acid, 5d

A mixture of 45c (202 mg, 0.766 mmol), LiOH (74 mg, 3.06 mmol), THF (2 mL), MeOH (2 mL) and H₂O (2 mL) was stirred at room temperature for 4 h. The reaction mixture was acidified with 15% citric acid (10 mL) and extracted with EtOAc. The extracts were washed with brine, dried over Na₂SO₄, and concentrated to give 177 mg of 45d.

C. 1-(1-{[6-(3-Chlorophenoxy)pyridin-3-yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine, Cpd 519

A mixture of 45d (60 mg, 0.24 mmol), 2c (101 mg, 0.36 mmol), HATU (137 mg, 0.36 mmol), Et₃N (0.5 mL), and DMF (3 mL) was stirred at room temperature overnight. The mixture was poured into water (30 mL) and extracted with EtOAc. The extracts were washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by flash column chromatography (silica gel, 5% MeOH/CH₂Cl₂) to give 50 mg of Cpd 519. ¹H NMR (CDCl₃): δ 8.35-8.49 (m, 1H), 8.06 (dd, J=8.5, 2.1 Hz, 1H), 7.32-7.49 (m, 6H), 7.14-7.27 (m, 2H), 6.94-7.11 (m, 2H), 4.24 (br. s., 1H), 4.15 (br. s., 2H), 4.00-4.14 (m, 2H), 3.65-3.94 (m, 2H), 3.37-3.60 (m, 2H), 3.16-3.33 (m, 1H), 2.44 (br. s., 4H). MS m/z (M+H⁺) 477.0.

Following the procedure described above for Example 45, Steps A and B, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared.

Following the procedure described above for Example 45, Step C, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared.

Cpd Cpd Name and Data 514 1-(Phenylcarbonyl)-4-[1-({6-[3- (trifluoromethyl)phenoxy]pyridin-3-yl}carbonyl)azetidin-3- yl]piperazine MS m/z (M + H⁺) 511.0 521 1-(1-{[6-(2-Chlorophenoxy)pyridin-3-yl]carbonyl}azetidin- 3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 477.0 683 1-(1-{[6-(3-Chlorophenoxy)pyridin-3-yl]carbonyl}azetidin- 3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 484.0 660 1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({6-[3- (trifluoromethyl)phenoxy]pyridin-3-yl}carbonyl)azetidin-3- yl]piperazine MS m/z (M + H⁺) 518.0 708 1-(1-{[6-(2-Chlorophenoxy)pyridin-3-yl]carbonyl}azetidin- 3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 484.0 878 1-[1-({6-[2-Fluoro-5-(trifluoromethyl)phenoxy]pyridin-3- yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 536.0

Example 45a

Following the procedure described above for Example 1, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared.

Cpd Cpd Name and Data 803 1-(1-{[6-(3-Chlorophenoxy)pyridin-3-yl]carbonyl}azetidin- 3-yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 504.0 689 1-(1,3-Thiazol-4-ylcarbonyl)-4-[1-({6-[3- (trifluoromethyl)phenoxy]pyridin-3-yl}carbonyl)azetidin-3- yl]piperazine MS m/z (M + H⁺) 518.0 811 1-(1-{[6-(2-Chlorophenoxy)pyridin-3-yl]carbonyl}azetidin- 3-yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 484.0

Example 46

A. 1-(4-Chloro-phenyl)-2-methyl-pent-1-en-3-one, 46b

To 4-chlorobenzaldehyde 46a (99.6 mmol, 14 g) in water (44 mL) was added KOH (44.6 mmol, 2.5 g). The mixture was heated at 65° C. and 3-pentanone (99.6 mmol, 8.58 g) was added dropwise over 10 min. After refluxing for 8 h, the reaction mixture was cooled to room temperature and stirred overnight. Following addition of 260 mL 1N aqueous HCl, the mixture was extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated. The crude product was purified by flash column chromatography (silica gel, 5% EtOAc/heptane) to give 8.59 g of 46b.

B. Ethyl 6-(4-chloro-phenyl)-3,5-dimethyl-2,4-dioxo-hex-5-enoate, 46c

To a solution of LiHMDS ON solution in THF, 5.48 mmol, 5.17 mL) in THF (16 mL) at −78° C. was added a solution of 46b (4.98 mmol, 1.04 g) in THF (2.5 mL) drop wise. After stirring at −78° C. for 1 h, the mixture was treated with a solution of diethyl oxalate (4.98 mmol, 0.73 g) in THF (2.5 mL). After stirring at −78° C. for 1 h, then the mixture was warmed up to room temperature and stirred overnight. The solvent was evaporated and the crude product was taken up in EtOAc, and washed with 1N HCl and brine. The organic layer was dried over Na₂SO₄ and concentrated to give 1.5 g of 46c.

C. 5-[2-(4-chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylate, 46e

A mixture of 46c (15.6 mmol, 4.82 g), 2,4-dichlorophenylhydrazine 46d (17.2 mmol, 3.67 g), K₂CO₃ (17.2 mmol, 2.37 g) and EtOH (137 mL) was stirred at 70° C. overnight. The solid was filtered off and washed with EtOH. The filtrates were concentrated and purified by flash column chromatography (silica gel, 5% EtOAc/heptane) to give 2.25 g of 46e.

D. 5-[2-(4-Chloro-phenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid, 46f

The mixture of 46e (3.34 mmol, 1.5 g), LiOH (13.3 mmol, 319 mg), THF (7 mL), MeOH (7 mL), and H₂O (37 mL) was stirred at room temperature for 4 h. The mixture was acidified with 1N HCl to pH=5 and extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated to give 46f (202 mg).

E. 5-[2-(4-Chlorophenyl)-1-methyl-vinyl]-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid, Cpd 1010

To a solution of 46f (0.138 mmol, 60 mg) in CH₂Cl₂ and THF was added SOCl₂ (2 N solution in THF, 0.414 mmol, 0.212 mL). After refluxing for 4 h, the mixture was concentrated and dried under vacuum for 1 h. In another flask was added 5e (0.18 mmol, 52 mg), CH₂Cl₂ (3 mL), and DIPEA (0.69 mmol, 0.12 mL). To this solution was added the crude product from the SOCl₂ reaction dissolved in CH₂Cl₂ (1 mL). After stirring at room temperature for 1 h, the mixture was diluted with CH₂Cl₂ (15 mL), washed with 3N NaOH aqueous solution (30 mL) and brine (30 mL), dried over Na₂SO₄, and concentrated. The crude product was purified by flash column chromatography (silica gel, 4% MeOH/CH₂Cl₂) to give 74 mg of Cpd 1010. ¹H NMR (CDCl₃): δ 7.87 (d, J=3.5 Hz, 1H), 7.55 (t, J=2.3 Hz, 2H), 7.33-7.36 (m, 2H), 7.30 (d, J=8.6 Hz, 2H), 7.13 (d, J=8.6 Hz, 2H), 6.41 (s, 1H), 4.49-4.62 (m, 2H), 4.41 (dd, J=10.4, 5.3 Hz, 2H), 4.22 (dd, J=10.0, 7.2 Hz, 1H), 4.04-4.10 (m, 1H), 3.87 (br. s., 1H), 3.82 (br. s., 1H), 3.18-3.26 (m, 1H), 2.41-2.58 (m, 4H), 2.39 (s, 3H), 1.88 (s, 3H). MS m/z (M+H⁺) 657.0.

Following the procedure described above for Example 46, Steps A-D or B-D, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared.

Following the procedure described above for Example 46, Step E, or Example 1, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared.

Cpd Cpd Name and Data 1011 1-[1-({5-[(E)-2-(4-Chlorophenyl)-1-methylethenyl]-1-(2,4- dichlorophenyl)-4-methyl-1H-pyrazol-3- yl}carbonyl)azetidin-3-yl]-4-(1H-pyrrol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 639.2 1018 (7E)-7-[(4-Chlorophenyl)methylidene]-1-(2,4- dichlorophenyl)-3-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4,5,6,7- tetrahydro-1H-indazole MS m/z (M + H⁺) 669.0 1019 (7E)-7-[(4-Chlorophenyl)methylidene]-1-(2,4- dichlorophenyl)-3-({3-[4-(1H-pyrrol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4,5,6,7- tetrahydro-1H-indazole MS m/z (M + H⁺) 651.2 1021 (7Z)-1-(2,4-Dichlorophenyl)-7-[(4- fluorophenyl)methylidene]-3-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,4,6,7- tetrahydrothiino[4,3-c]pyrazole MS m/z (M + H⁺) 671.0 1024 (7Z)-1-(2,4-Dichlorophenyl)-7-[(4- fluorophenyl)methylidene]-3-({3-[4-(1H-pyrrol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,4,6,7- tetrahydrothiino[4,3-c]pyrazole MS m/z (M + H⁺) 651.2 1267 1-(2,4-Dichlorophenyl)-3-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4,5,6,7- tetrahydro-1H-indazole MS m/z (M + H⁺) 645.2 1309 1-(2,4-Dichlorophenyl)-3-({3-[4-(1H-pyrrol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4,5,6,7- tetrahydro-1H-indazole MS m/z (M + H⁺) 627.2 1023 (7E)-7-[(4-Chlorophenyl)methylidene]-1-(2,4- dichlorophenyl)-3-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4,5,6,7- tetrahydro-1H-indazole MS m/z (M + H⁺) 669.1 1304 1-(2,4-Dichlorophenyl)-3-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4,5,6,7- tetrahydro-1H-indazole MS m/z (M + H⁺) 545.2

Example 46a

Following the procedure described above for Example 1c, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data Salt Form 1012 1-[1-({5-[(E)-2-(4-Chlorophenyl)-1- N-TFA methylethenyl]-1-(2,4-dichlorophenyl)-4-methyl- 1H-pyrazol-3-yl}carbonyl)azetidin-3-yl]-4- (trifluoroacetyl)piperazine MS m/z (M + H⁺) 642.9 1020 (7E)-7-[(4-Chlorophenyl)methylidene]-1-(2,4- N-TFA dichlorophenyl)-3-({3-[4- (trifluoroacetyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-4,5,6,7-tetrahydro-1H-indazole MS m/z (M + H⁺) 654.0 1022 (7Z)-1-(2,4-Dichlorophenyl)-7-[(4- N-TFA fluorophenyl)methylidene]-3-({3-[4- (trifluoroacetyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-1,4,6,7-tetrahydrothiino[4,3- c]pyrazole MS m/z (M + H⁺) 654.1 1311 1-(2,4-Dichlorophenyl)-3-({3-[4- N-TFA (trifluoroacetyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-4,5,6,7-tetrahydro-1H-indazole MS m/z (M + H⁺) 530.2

Example 47

4-(((2-fluorophenyl)amino)methyl)benzoic acid, 47c

A mixture of 4-formylbenzoic acid 47a (3.33 mmol, 500 mg), 2-fluoroaniline 47b (3.33 mmol, 370 mg), and decaborane (1 mmol, 122 mg) in 8 mL of MeOH was stirred at room temperature for 15 min. The mixture was concentrated and purified by preparative reverse-phase chromatography to afford 0.81 g (99%) of 47c.

Following the procedure described above for Example 47, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared.

Following the procedure described above for Example 1 or Example 9, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared.

Cpd Cpd Name and Data 553 2-Fluoro-N-[4-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)benzyl]aniline MS m/z (M + H⁺) 473.1 529 N-Benzyl-2-chloro-5-methoxy-4-({3-[4- (phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)aniline MS m/z (M + H⁺) 520.2 530 N-(4,4-Difluorocyclohexyl)-4-({3-[4- (phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)aniline MS m/z (M + H⁺) 483.2 561 2-Fluoro-N-[3-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)benzyl]aniline MS m/z (M + H⁺) 473.1 556 2,6-Difluoro-N-[4-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)benzyl]aniline MS m/z (M + H⁺) 491.0 542 N-Benzyl-2-iodo-4-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)aniline MS m/z (M + H⁺) 581.0 557 2,3,4-Trifluoro-N-[4-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)benzyl]aniline MS m/z (M + H⁺) 509.2 1005 2-Fluoro-N-[3-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)benzyl]aniline MS m/z (M + H⁺) 480.3

Example 48

4-(Cyclohexanecarboxamido)benzoic acid, 48d

A mixture of 4-aminobenzoic acid 48a (1.98 mmol, 300 mg), cyclohexanecarbonyl chloride 48b (1.98 mmol, 291 mg), and Et₃N (2.52 mmol, 0.43 mL) in 6 mL of THF was stirred at room temperature overnight. 1N aqueous NaOH (7.9 mmol, 7.9 mL) was added to the mixture (containing methyl 4-(cyclohexanecarboxamido)benzoate 48c) and the reaction mixture was stirred for 5 h at room temperature. The THF was removed by rotary evaporation and 1N aqueous HCl was added to precipitate the product, which was filtered to give 480 mg (92%) of 48d.

Following the procedure described above for Example 9, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compound of the present invention was prepared.

Cpd Cpd Name and Data 709 N-[4-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)phenyl]cyclohexanecarboxamide MS m/z (M + H⁺) 482.1

Example 49

2-(4,4-Difluoropiperidin-1-yl)benzo[d]thiazole-6-carboxylic acid, 49d

A mixture of ethyl 2-bromo-benzo[d]thiazole-6-carboxylate 49a (1.75 mmol, 500 mg), 4,4-difluoropiperidine 49b (1.92 mmol, 303 mg), and Cs₂CO₃ (5.24 mmol, 1.71 g) in 15 mL of CH₃CN was refluxed overnight. The suspension was cooled to room temperature and 15 mL of water was added to the mixture (containing ethyl 2-(4,4-difluoropiperidin-1-yl)benzo[d]thiazole-6-carboxylate 49c). The reaction mixture was heated at 60° C. for 18 h. After cooling, the mixture was acidified using 3N aqueous HCl and the resulting precipitate was filtered to give 575 mg (99%) of 49d. MS m/z (M+H⁺) 299.1.

Following the procedure described above for Example 9, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compound of the present invention was prepared.

Cpd Cpd Name and Data 671 2-(4,4-Difluoropiperidin-1-yl)-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- benzothiazole MS m/z (M + H⁺) 533.2

Example 50

3-Chloro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole, Cpd 1365

To a solution of Cpd 487 (0.2 mmol, 100 mg) in CCl₄ (4 mL) and CH₂Cl₂ (4 mL) was added NCS (0.25 mmol, 33 mg). The reaction mixture was stirred at room temperature for 4 h. It was then diluted with CH₂Cl₂ and washed with 1N aqueous NaOH and H₂O, dried over Na₂SO₄, and concentrated. Purification by flash column chromatography (silica gel, 3% MeOH/CH₂Cl₂) gave 51 mg of Cpd 1365. MS m/z (M+H⁺) 524.

Example 51

A. 1-(3-cyano-4-fluoro-phenyl)-indole-5-carboxylic acid, 51a and 1-(3-carbamoyl-4-fluoro-phenyl)-indole-5-carboxylic acid, 51b

Intermediates 51a and 51b were prepared according to Example 9e, and were obtained as a ˜1:1 mixture.

B. 2-Fluoro-5-[5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzonitrile, Cpd 1417 and 2-fluoro-5-[5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol-1-yl]benzamide, Cpd 1418

Cpd 1417 and Cpd 1418 were prepared according to Example 9 from 5a bis HCl salt (0.22 mmol, 72 mg), the ˜1:1 mixture of 51a and 51b (0.19 mmol, 54 mg), HATU (0.22 mmol, 85 mg), and Et₃N (1.11 mmol, 0.15 mL) in 4 mL of CH₂Cl₂. After workup, purification by flash column chromatography (silica gel, 3-4% MeOH/CH₂Cl₂) gave 28 mg (59%) of Cpd 1417 followed by 15 mg (31%) of Cpd 1418. Cpd 1417: MS m/z (M+H⁺) 515. Cpd 1418: MS m/z (M+H⁺) 533.

Example 52

A. Methyl 5-Phenyl-benzo[b]thiophene-2-carboxylate, 52b

A mixture of compound 52a (542.3 mg, 2 mmol), phenyl boronic acid 1x (268.2 mg, 2.2 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (98 mg, 0.12 mmol), and K₂CO₃ (414.6 mg, 3 mmol), in a dioxane (4 mL)/water (1 mL) mixture, was placed in a capped vial and heated at 80° C. overnight. The reaction mixture was then diluted with EtOAc and water. The organic layer was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 2-10% EtOAc/heptane) to give compound 52b (510 mg). MS m/z (M+H⁺) 269.1.

B. 5-Phenyl-benzo[b]thiophene-2-carboxylic acid, 52c

A solution of compound 52b (510 mg, 1.9 mmol) and LiOH.H₂O (319 mg, 7.6 mmol) in THF/H₂O (10/10 mL) was stirred at room temperature overnight. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH˜4 and extracted with CH₂Cl₂. The organic solution was dried over Na₂SO₄ and concentrated to give 52c (479 mg), which was used in the next reaction without further purification. MS m/z (M+H⁺) 255.0.

C. 3-Fluoro-5-phenyl-benzo[b]thiophene-2-carboxylic acid, 52d

To a solution of compound 52c (507 mg, 1.99 mmol) in THF (8 mL) at −70° C. was added n-BuLi (1.6 M in hexane, 2.62 mL, 4.19 mmol). The mixture was stirred at −70° C. for 1 h; then a solution of N-fluorobenzenesulfonimide (817.3 mg, 2.59 mmol) in THF (2 mL) was slowly added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The resulting mixture was partitioned between dilute aqueous HCl and EtOAc. The organic solution was washed with water and brine, dried over Na₂SO₄, and concentrated. The residue was tritrated from CH₂Cl₂, filtered and dried the solid to give compound 52d (391.9 mg). MS m/z (M+H⁺) 273.0.

D. 3-Fluoro-5-phenyl-benzo[b]thiophene-2-carbonyl chloride, 52e

To a solution of compound 52d (136.2 mg, 0.5 mmol) in CH₂Cl₂ (5 mL) at room temperature was added (COCl)₂ (0.064 mL, 0.75 mmol), followed by DMF (0.01 mL, 0.125 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated to give compound 52e (light pink powder), which was used in the next reaction without further purification.

E. 1-{1-[(3-Fluoro-5-phenyl-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 1315

To a solution of compound 5e (42.7 mg, 0.131 mmol) and Et₃N (0.07 mL, 0.5 mmol) in CH₂Cl₂ (2 mL) at 0° C. was slowly added a solution of compound 52e (36.3 mg, 0.125 mmol) in CH₂Cl₂ (1 mL). The reaction was stirred at 0° C. for 2 h, diluted with CH₂Cl₂, and washed with aqueous NaHCO₃. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by flash column chromatography (silica gel, 2% MeOH/EtOAc) to give compound Cpd 1315 (16.7 mg). ¹H NMR (400 MHz, CDCl₃): δ 7.98 (d, J=1.2 Hz, 1H), 7.89 (d, J=3.2 Hz, 1H), 7.80-7.86 (m, 1H), 7.73 (dd, J=8.6, 1.7 Hz, 1H), 7.62-7.68 (m, 2H), 7.55 (d, J=3.2 Hz, 1H), 7.46-7.53 (m, 2H), 7.37-7.44 (m, 1H), 4.22-4.67 (m, 5H), 4.05-4.20 (m, 1H), 3.77-4.01 (m, 2H), 3.25-3.37 (m, 1H), 2.42-2.68 (m, 4H). MS m/z (M+H⁺) 507.0.

Following the procedure described above for Example 52, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1092 1-[1-({3-Fluoro-5-[4-(trifluoromethyl)phenyl]-1- benzothiophen-2-yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 575.1. 1063 1-[1-({3-Fluoro-6-[4-(trifluoromethyl)phenyl]-1- benzothiophen-2-yl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 575.1.

Example 53

A. 1-tert-Butyl 6-methyl 3-(4-fluorophenyl)-1H-indole-1,6-dicarboxylate, 53c

A mixture of compound 53a (1.00 g, 2.49 mmol), 4-fluorophenyl boronic acid 53b (523 mg, 3.74 mmol), Pd(OAc)₂ (44.8 mg, 0.2 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos, 204.7 mg, 0.5 mmol), and K₃PO₄ (1.06 g, 4.99 mmol), in toluene (5 mL) was placed in a capped vial and heated at 90° C. under N₂ for 3 h. The reaction mixture was then diluted with EtOAc and water. The organic layer was washed with brine, concentrated under reduced pressure, and purified by flash column chromatography (silica gel, 2-10% EtOAc/heptane) to give compound 53c as a light yellow solid, which was further recrystallized from heptane to obtain white solid (707 mg). MS m/z (M+H⁺) 370.2.

B. Methyl 3-(4-fluorophenyl)-1H-indole-6-carboxylate, 53d

To a solution of compound 53c (705 mg, 1.91 mmol) in CH₂Cl₂ (4 mL) was added trifluoroacetic acid (1.5 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated to give compound 53d (603.3 mg) as a white solid. MS m/z (M+H⁺) 270.1.

C. 3-(4-Fluoro-phenyl)-1H-indole-6-carboxylic acid, 53e

A solution of compound 53d (303 mg, 0.79 mmol), and LiOH.H₂O (132.7 mg, 3.16 mmol) in THF/H₂O (10 mL/10 mL) was stirred at 45° C. for 5 h. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH˜4 and extracted with CH₂Cl₂. The organic solution was dried over Na₂SO₄ and concentrated to give 53e (249 mg), which was used in the next reaction without further purification. MS m/z (M+H⁺) 256.0.

D. 3-(4-Fluorophenyl)-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole, Cpd 1317

To a mixture of compound 5e (42.9 mg, 0.132 mmol), compound 53e (30.6 mg, 0.12 mmol), and Et₃N (0.084 mL, 0.6 mmol) in CH₂Cl₂ (1 mL) at room temperature was added HATU (70 mg, 0.168 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with CH₂Cl₂ and H₂O, washed with aq. NaHCO₃ and brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 2-4% MeOH/EtOAc) to give Cpd 1317 (45.4 mg). ¹H NMR (400 MHz, CDCl₃): δ 8.56 (br. s., 1H), 7.83-7.94 (m, 3H), 7.57-7.65 (m, 2H), 7.55 (d, J=3.2 Hz, 1H), 7.46 (d, J=2.4 Hz, 1H), 7.40-7.45 (m, 1H), 7.13-7.20 (m, 2H), 4.07-4.66 (m, 6H), 3.76-4.01 (m, 2H), 3.21-3.36 (m, 1H), 2.38-2.64 (m, 4H). MS m/z (M+H⁺) 490.2.

Following the procedure described above for Example 53, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Following the procedure described above for Example 53, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1316 3-Phenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 472.2. 1319 3-(3-Fluorophenyl)-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 490.2.

Example 53a

E. Methyl 3-(4-Fluoro-phenyl)-1-methyl-1H-indole-6-carboxylate, 53f

To a solution of compound 53d (300 mg, 0.78 mmol) in DMF (3 mL) was added NaH (60% in mineral oil, 68.9 mg, 1.72 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min, then CH₃I (0.053 mL, 0.86 mmol) was added and stirring continued at 0° C. for another 1 h. The resulting mixture was diluted with EtOAc and water. The organic layer was washed with brine and concentrated. The residue was recrystallized from heptane, filtered and dried the solid to give compound 53f (265 mg) as a light yellow solid. MS m/z (M+H⁺) 284.1.

F. 3-(4-Fluoro-phenyl)-1-methyl-1H-indole-6-carboxylic acid, 53g

To a solution compound 53f (264 mg, 0.93 mmol), and LiOH.H₂O (156.4 mg, 3.73 mmol) in THF/H₂O (10 mL/10 mL) was stirred at 45° C. for 5 h. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH˜4 and extracted with CH₂Cl₂. The organic solution was dried over Na₂SO₄ and concentrated to give compound 53g (252 mg), which was used in the next reaction without further purification. MS m/z (M+H⁺) 270.1.

Following the procedure described above for Example 53a and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compound was prepared:

Following the procedure described above for Example 53 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1318 3-(4-Fluorophenyl)-1-methyl-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, J = 2.9 Hz, 1H), 7.79-7.87 (m, 2H), 7.51-7.63 (m, 3H), 7.39 (d, J = 8.3 Hz, 1H), 7.31 (s, 1H), 7.15 (t, J = 8.7 Hz, 2H), 4.21-4.67 (m, 5H), 4.08-4.21 (m, 1H), 3.89 (s, 3H), 3.77-3.98 (m, 2H), 3.19-3.35 (m, 1H), 2.36-2.65 (m, 4H) MS m/z (M + H⁺) 504.1 1142 3-(3-Fluorophenyl)-1-methyl-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 504.1

Example 54

A. Ethyl 1-Methyl-3-phenyl-1H-indazole-5-carboxylate, 54b

A mixture of compound 54a (300 mg, 0.91 mmol), phenyl boronic acid 1x (133 mg, 1.09 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (40 mg, 0.055 mmol), and K₂CO₃ (251.2 mg, 1.82 mmol), in a toluene (2 mL)/water (0.4 mL) mixture, was placed in a capped vial and heated at 90° C. overnight. The reaction mixture was then diluted with EtOAc and water. The organic layer was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 2-10% EtOAc/Heptanes) to give compound 54b (231 mg). MS m/z (M+H⁺) 281.1.

B. 1-Methyl-3-phenyl-1H-indazole-5-carboxylic acid, 54c

A solution compound 54b (230 mg, 0.58 mmol), and LiOH.H₂O (98 mg, 2.33 mmol) in THF/H₂O (10/10 mL) was stirred at 45° C. for 8 h. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH˜4 and extracted with CH₂Cl₂. The organic solution was dried over Na₂SO₄ and concentrated to give 54c (206 mg), which was used in the next reaction without further purification. MS m/z (M+H⁺) 253.1.

C. 1-Methyl-3-phenyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indazole, Cpd 1137

To a mixture of compound 5e (42.9 mg, 0.132 mmol), compound 54c (30.3 mg, 0.12 mmol), and Et₃N (0.084 mL, 0.6 mmol) in CH₂Cl₂ (1 mL) at room temperature was added HATU (70 mg, 0.168 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with CH₂Cl₂ and H₂O, washed with aq. NaHCO₃ and brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 2-4% MeOH/EtOAc) to give Cpd 1137 (48.1 mg). ¹H NMR (400 MHz, CDCl₃): δ 8.32 (s, 1H), 7.94 (d, J=7.3 Hz, 2H), 7.88 (d, J=3.2 Hz, 1H), 7.74 (d, J=9.5 Hz, 1H), 7.49-7.58 (m, 3H), 7.39-7.48 (m, 2H), 4.16 (s, 3H), 4.09-4.62 (m, 6H), 3.86 (m, 2H), 3.21-3.33 (m, 1H), 2.39-2.63 (m, 4H). MS m/z (M+H⁺) 487.2.

Following the procedure described above for Example 54 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Following the procedure described above for Example 54 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1170 3-(3-Fluorophenyl)-1-methyl-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indazole MS m/z (M + H⁺) 505.2 1195 3-(4-Fluorophenyl)-1-methyl-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indazole MS m/z (M + H⁺) 505.2 1130 4-Phenyl-7-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)quinazoline MS m/z (M + H⁺) 485 1086 7-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-4-[4-(trifluoromethyl)phenyl]quinazoline MS m/z (M + H⁺) 553 604 4-Phenyl-7-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)quinazoline MS m/z (M + H⁺) 478 597 7-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-4-[4-(trifluoromethyl)phenyl]quinazoline MS m/z (M + H⁺) 546

Example 55

A. Methyl 2,3-dihydro-1H-indole-5-carboxylate, 55a

To a solution of methyl 1H-indole-5-carboxylate 1j (2 g, 11.4 mmol) in glacial acetic acid (15 mL) at 0° C. was added sodium cyanoborohydride (1.08 g, 17.2 mmol) slowly. The mixture was allowed to warm up and stirred at room temperature for 2 h. Water was added to the resulting mixture at 0° C., and pH of the solution was adjusted to ˜12 with 1N aqueous NaOH. The mixture was extracted with CH₂Cl₂ and the organic layer was washed with brine and dried over Na₂SO₄. The solution was concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/heptane) to give compound 55a (1.79 g). MS m/z (M+H⁺) 178.1.

B. Methyl 1-(4-fluoro-phenyl)-2,3-dihydro-1H-indole-5-carboxylate, 55b, and 1-(4-fluoro-phenyl)-2,3-dihydro-1H-indole-5-carboxylic acid, 55c

A mixture of compound 55a (500 mg, 2.82 mmol), 1-bromo-4-fluoro-benzene 1k (0.31 mL, 2.82 mmol), Pd₂(dba)₃ (129 mg, 0.14 mmol), BINAP (132 mg, 0.21 mmol), and sodium t-butoxide (325 mg, 3.39 mmol) in toluene (25 mL) was placed in a capped vial and heated at 80° C. overnight. The reaction mixture was then diluted with EtOAc and water, and the water layer was basified to pH˜8 with 1N aqueous NaOH. The organic layer was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 5-30% EtOAc/heptane) to give compound 55b (145 mg), MS m/z (M+H⁺) 272.1, and compound 55c (232 mg), MS m/z (M+H⁺) 258.0.

C. 1-(4-Fluoro-phenyl)-2,3-dihydro-1H-indole-5-carboxylic acid, 55d

A solution of compound 55b (144 mg, 0.53 mmol) and LiOH.H₂O (89.1 mg, 2.12 mmol) in THF/H₂O (5 mL/5 mL) was stirred at 45° C. overnight. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH˜4 and extracted with CH₂Cl₂. The organic solution was dried over Na₂SO₄ and concentrated to give 55d (138 mg), which was used in the next reaction without further purification. MS m/z (M+H⁺) 258.0.

D. 1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3-dihydro-1H-indole, Cpd 885

To a mixture of compound 5e (42.9 mg, 0.132 mmol), compound 55d (30.9 mg, 0.12 mmol), and Et₃N (0.084 mL, 0.6 mmol) in CH₂Cl₂ (1 mL) at room temperature was added HATU (70 mg, 0.168 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with CH₂Cl₂ and washed with H₂O, aqueous NaHCO₃ and brine, and then dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 2-4% MeOH/EtOAc) to give compound Cpd 885 (44.4 mg). ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, J=3.2 Hz, 1H), 7.55 (d, J=3.2 Hz, 1H), 7.51 (d, J=1.2 Hz, 1H), 7.38 (dd, J=8.3, 1.7 Hz, 1H), 7.16-7.25 (m, 2H), 7.03-7.12 (m, 2H), 6.88 (d, J=8.3 Hz, 1H), 4.05-4.67 (m, 6H), 3.99 (t, J=8.6 Hz, 2H), 3.76-3.94 (m, 2H), 3.20-3.30 (m, 1H), 3.16 (t, J=8.6 Hz, 2H), 2.37-2.64 (m, 4H); MS m/z (M+H⁺) 492.1.

Following the procedure described above for Example 55 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compound was prepared:

Following the procedure described above for Example 55 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 884 1-(4-Fluorophenyl)-4-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3- dihydro-1H-indole MS m/z (M + H⁺) 492.1 1081 1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3- dihydro-1H-indole MS m/z (M + H⁺) 492.1 1099 1-(4-Fluorophenyl)-5-({3-[4-(1H-pyrrol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3- dihydro-1H-indole MS m/z (M + H⁺) 474.1

Example 55a

E. Methyl 1-benzyl-2,3-dihydro-1H-indole-5-carboxylate, 55e

A solution of methyl 2,3-dihydro-1H-indole-5-carboxylate HCl salt 55a (88.6 mg, 0.42 mmol), and benzaldehyde 23a (0.060 mL, 0.55 mmol) in CH₂Cl₂ (4 mL) was stirred at room temperature for 30 min Sodium triacetoxyborohydride (159 mg, 0.75 mmol) was added to the mixture and stirring was continued for 2 h. Water was added to the resulting mixture at 0° C., and pH of the solution was adjusted to ˜8 with 1N aqueous NaOH. The mixture was extracted with CH₂Cl₂ and the organic layer was washed with brine and dried over Na₂SO₄. The solution was concentrated and purified by flash column chromatography (silica gel, 10-25% EtOAc/Heptanes) to give 55e (81.3 mg). MS m/z (M+H⁺) 268.0.

F. 1-Benzyl-2,3-dihydro-1H-indole-5-carboxylic acid, 55f

A solution of compound 55e (80.2 mg, 0.3 mmol), and LiOH.H₂O (50.4 mg, 1.2 mmol) in THF/H₂O (1.2/1.2 mL) was stirred at room temperature overnight. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH ˜4 and extracted with CH₂Cl₂. The organic solution was dried over Na₂SO₄ and concentrated to give 55f (60 mg), which was used in the next reaction without further purification. MS m/z (M+H⁺) 254.1.

G. 1-Benzyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3-dihydro-1H-indole, Cpd 994

To a solution of compound 5e (89.5 mg, 0.261 mmol), compound 55f (60 mg, 0.237 mmol), and EDC (68.1 mg, 0.356 mmol) in CH₂Cl₂ (5 mL) was added Et₃N (0.1 mL, 0.711 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with CH₂Cl₂ and H₂O and the water layer was acidified to pH ˜6 with 1 N aqueous HCl. The organic solution was dried over Na₂SO₄ and concentrated. The residue was purified by reverse phase chromatography to give Cpd 994 as a TFA salt (40.4 mg). ¹H NMR (400 MHz, CD₃OD): δ 7.98 (d, J=3.2 Hz, 1H), 7.89 (d, J=3.2 Hz, 1H), 7.36-7.44 (m, 2H), 7.29-7.36 (m, 4H), 7.22-7.29 (m, 1H), 6.52 (d, J=8.3 Hz, 1H), 4.39-4.91 (m, 6H), 4.38 (s, 2H), 3.99-4.23 (m, 3H), 3.48 (t, J=8.6 Hz, 2H), 3.42 (br. s., 4H), 3.01 (t, J=8.6 Hz, 2H). MS m/z (M+H⁺) 488.1.

Following the procedure described above for Example 55a and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Following the procedure described above for Example 55a and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 881 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-[3-(trifluoromethyl)benzyl]-2,3-dihydro- 1H-indole MS m/z (M + H⁺) 556.0 882 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-[4-(trifluoromethyl)benzyl]-2,3-dihydro- 1H-indole MS m/z (M + H⁺) 556.0

Example 55b

H. 1-Benzoyl-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester, 55g

To a solution of methyl 2,3-dihydro-1H-indole-5-carboxylate HCl salt 55a (64.1 mg, 0.3 mmol), and benzoyl chloride 1t (0.042 mL, 0.36 mmol) in CH₂Cl₂ (1 mL) was added Et₃N (0.13 mL, 0.9 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The resulting mixture was partitioned between CH₂Cl₂ and H₂O. The organic solution was dried over Na₂SO₄ and concentrated. Purification of the residue by flash column chromatography (silica gel, 10-20% EtOAc/Heptanes) gave 55g (88 mg). MS m/z (M+H⁺) 282.0.

I. 1-Benzoyl-2,3-dihydro-1H-indole-5-carboxylic acid, 55h

A solution of compound 55g (87 mg, 0.31 mmol), and LiOH.H₂O (52 mg, 1.24 mmol) in THF/H₂O (2/2 mL) was stirred at room temperature overnight. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH ˜6 and extracted with CH₂Cl₂. The organic solution was dried over Na₂SO₄ and concentrated to give 55h (82 mg), which was used in the next reaction without further purification. MS m/z (M+H⁺) 268.0.

J. 1-(Phenylcarbonyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3-dihydro-1H-indole, Cpd 724

To a solution of compound 5e (115.9 mg, 0.34 mmol), compound 55h (82 mg, 0.31 mmol) and EDC (87.9 mg, 0.46 mmol) in CH₂Cl₂ (5 mL) was added Et₃N (0.13 mL, 0.92 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with CH₂Cl₂ and H₂O and the water layer was acidified to pH ˜6 with 1 N aqueous HCl. The organic solution was dried over Na₂SO₄ and concentrated. The residue was purified by flash column chromatography (silica gel, 2% MeOH/EtOAc) to give compound Cpd 724 (64.4 mg). ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, J=3.2 Hz, 1H), 7.31-7.63 (m, 9H), 4.38-4.63 (m, 2H), 4.03-4.37 (m, 6H), 3.74-3.96 (m, 2H), 3.20-3.29 (m, 1H), 3.16 (t, J=8.3 Hz, 2H), 2.38-2.61 (m, 4H). MS m/z (M+H⁺) 502.0.

Following the procedure described above for Example 55b and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compound was prepared:

Following the procedure described above for Example 55b and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compound of the present invention was prepared:

Cpd Cpd Name and Data 773 1-(Cyclopropylcarbonyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2,3- dihydro-1H-indole MS m/z (M + H⁺) 466.0

Example 56

A. Methyl 3-Benzyl-1-methyl-1H-indole-6-carboxylate, 56c

To a solution of compound 56a (500 mg, 2.64 mmol) and benzyl chloride 56b (0.33 mL, 2.91 mmol) in dioxane (5 mL) was added silver oxide (673.6 mg, 2.91 mmol). The mixture was stirred at 80° C. overnight. The resulted mixture was filtered through celite and washed with EtOAc. The filtrate was concentrated and purified by flash column chromatography (silica gel, 20-60% CH₂Cl₂/Heptanes) to give compound 56c (168 mg). MS m/z (M+H⁺) 280.2.

B. 3-Benzyl-1-methyl-1H-indole-6-carboxylic acid, 56d

To a solution compound 56c (168 mg, 0.60 mmol), and LiOH.H₂O (101 mg, 2.41 mmol) in THF/H₂O (3/3 mL) was stirred at room temperature for 6 h. Concentrated the resulted mixture, extracted the residue with CH₂Cl₂, H₂O, acidified the water layer with 1N HCl(aq) to pH˜4. The organic solution was dried over Na₂SO₄ and concentrated to give 56d (172.2 mg), which was used in the next reaction without further purification. MS m/z (M+H⁺) 266.2.

C. 3-Benzyl-1-methyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole, Cpd 753

To a mixture of compound 5e (71.6 mg, 0.22 mmol), compound 56d (53.1 mg, 0.2 mmol), and Et₃N (0.14 mL, 1.0 mmol) in CH₂Cl₂ (1 mL) at room temperature was added HATU (106.5 mg, 0.28 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with CH₂Cl₂ and H₂O, washed with aqueous NaHCO₃ and brine, dried over Na₂SO₄, filtered, and concentrated. Purification of the residue by flash column chromatography (silica gel, 2-4% MeOH/EtOAc) gave compound Cpd 753 (20.8 mg). ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, J=2.4 Hz, 1H), 7.74 (s, 1H), 7.55 (d, J=2.7 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.15-7.35 (m, 6H), 6.89 (s, 1H), 4.06-4.60 (m, 8H), 3.79-3.98 (m, 2H), 3.78 (s, 3H), 3.17-3.31 (m, 1H), 2.35-2.64 (m, 4H). MS m/z (M+H⁺) 500.3.

Following the procedure described above for Example 56 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Following the procedure described above for Example 56 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1026 3-(4-Fluorobenzyl)-1-methyl-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 518.1 1027 3-(4-Fluorobenzyl)-1-methyl-6-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 518.1 1028 3-(4-Fluorobenzyl)-1-methyl-6-({3-[4-(1H-pyrrol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 500.1 1033 3-(3-Fluorobenzyl)-1-methyl-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole m/z (M + H⁺) 518.2

Example 57

5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3,3-tris[3-(trifluoromethyl)benzyl]-1,3-dihydro-2H-indol-2-one, Cpd 1430

To a solution of Cpd 918 from Example 9) (25 mg, 0.061 mmol) and K₂CO₃ (16.9 mg, 0.122 mmol) in DMF (0.8 mL) was added 3-trifluoromethyl-benzyl bromide (20.4 mg, 0.085 mmol). The mixture was stirred at room temperature overnight. The resulting mixture was extracted with EtOAc and H₂O. The organic solution was dried over Na₂SO₄ and concentrated. The residue was purified by reverse phase chromatography to give Cpd 1430 as a TFA salt (3.6 mg), MS m/z (M+H⁺) 885.9.

Following the procedure described above for Example 57 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1431 1,3,3-Tribenzyl-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- dihydro-2H-indol-2-one MS m/z (M + H⁺) 682.0 992 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-3,3-bis[3-(trifluoromethyl)benzyl]-1,3- dihydro-2H-indol-2-one MS m/z (M + H⁺) 728.0

Example 58

5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole, Cpd 911, and 1-(2,3-Dihydro-1H-indol-5-ylcarbonyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole, Cpd 988

To a solution of compound 5e (300 mg, 0.92 mmol), a mixture of 2,3-dihydro-1H-indole-5-carboxylic acid HCl salt 58a (101 mg, 0.51 mmol) and 1H-indole-5-carboxylic acid HCl salt 58b (100 mg, 0.51 mmol), and EDC (265 mg, 1.38 mmol) in CH₂Cl₂ (10 mL) was added Et₃N (0.39 mL, 2.77 mmol). The reaction mixture was stirred at room temperature overnight. The resulting mixture was extracted with CH₂Cl₂ and washed with H₂O. The organic solution was dried over Na₂SO₄ and concentrated. The residue was purified by reverse phase chromatography to give Cpd 911 as a TFA salt (89.4 mg) and Cpd 988 as a TFA salt (13.8 mg).

Cpd 911: ¹H NMR (400 MHz, CD₃OD): δ 10.93 (br. s., 1H), 7.98 (d, J=3.2 Hz, 1H), 7.95 (s, 1H), 7.89 (d, J=3.2 Hz, 1H), 7.47 (s, 2H), 7.36 (d, J=3.2 Hz, 1H), 6.57 (d, J=2.9 Hz, 1H), 4.25-4.84 (m, 6H), 3.91-4.15 (m, 4H), 2.80 (br. s., 4H). MS m/z (M+H⁺) 396.0. Cpd 988: ¹H NMR (400 MHz, CD₃OD): δ 7.98 (d, J=3.2 Hz, 1H), 7.88 (d, J=3.2 Hz, 1H), 7.85 (d, J=1.0 Hz, 1H), 7.58 (s, 1H), 7.27-7.56 (m, 5H), 6.56 (d, J=3.2 Hz, 1H), 4.29-4.89 (m, 6H), 4.20 (t, J=8.3 Hz, 2H), 3.96-4.15 (m, 3H), 3.32-3.43 (m, 4H), 3.17 (t, J=8.3 Hz, 2H). MS m/z (M+H⁺) 541.0.

Example 59

A. 3-Methyl-[1,1′-biphenyl]-4-carboxylic acid, 59b

The title compound 59b was prepared using the method described in Example 6, Step F, substituting 4-bromo-2-methylbenzoic acid 59a for Cpd 173 and substituting phenylboronic acid 1x for compound 6e. The crude product 59b was purified by reverse phase chromatography. MS m/z (M+H⁺) 213.1.

B. 1-{1-[(3-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine, Cpd 619

The title compound Cpd 619 was prepared using the method described in Example 9, substituting compound 59b for compound 9c and substituting compound 2c for compound 5e. The crude compound Cpd 619 was purified by reverse phase chromatography. MS m/z (M+H⁺) 440.1.

Following the procedure described above for Example 59 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Following the procedure described above for Example 59 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 613 1-{1-[(2-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 440.2 614 1-{1-[(3-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 444.1 615 1-{1-[(2-Methoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 456.1 612 1-{1-[(3-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 460.2 706 1-(1-{[4-(2,2,6,6-Tetramethyl-3,6-dihydro-2H-pyran-4- yl)phenyl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 495.3 1074 1-{1-[(3-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine 1H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.87 (d, 1H), 7.33-7.66 (m, 8H), 4.62-4.76 (m, 2H), 4.38-4.51 (m, 1H), 4.13-4.35 (m, 3H), 3.84-4.07 (m, 3H), 3.02-3.19 (m, 4H), 2.47 (s, 1H) MS m/z (M + H⁺) 447.1 1322 1-{1-[(2-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine 1H NMR (300 MHz, CD₃OD): δ 7.98 (d, 1H), 7.88 (d, 1H), 7.59 (s, 1H), 7.54 (dd, 1H), 7.27-7.49 (m, 6H), 4.61-4.78 (m, 3H), 4.39-4.61 (m, 2H), 4.33 (M, 1H), 3.88-4.11 (m, 3H), 3.10-3.26 (m, 4H), 2.30 (s, 3H) MS m/z (M + H⁺) 447.1 1405 1-{1-[(3-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine 1H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.87 (d, 1H), 7.36-7.73 (m, 8H), 4.23-4.76 (m, 6H), 3.85-4.07 (m, 3H), 3.04-3.20 (m, 4H) MS m/z (M + H⁺) 451.2 1377 1-{1-[(2-Methoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 463.2 1323 1-{1-[(3-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 467.1 1406 1-{1-[(2-Methylbiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 447.1 1108 1-{1-[(3-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-4-ylcarbonyl)piperazine 1H NMR (300 MHz, CD₃OD): δ 9.06 (s, 1H), 8.22 (d, 1H), 7.38-7.71 (m, 8H), 4.28-4.53 (m, 4H), 3.94-4.25 (m, 5H), 3.16-3.27 (m, 4H) MS m/z (M + H⁺) 451.1 1253 1-{1-[(2-Methoxybiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 463.2 1221 1-{1-[(3-Chlorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 467.1 1185 1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[2′- (trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3- yl)piperazine MS m/z (M + H⁺) 501.0 1278 1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[4′- (trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3- yl)piperazine MS m/z (M + H⁺) 501.0 1250 1-{1-[(4′-Methoxybiphenyl-3-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 563.0 1091 1-{1-[(4′-Methoxybiphenyl-3-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 463.0 1093 1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[3′- (trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3- yl)piperazine MS m/z (M + H⁺) 501.0 1124 1-{1-[(3′-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 451.0 1117 1-{1-[(2′,4′-Difluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine 1H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.87 (d, 1H), 7.80 (d, 1H), 7.66-7.75 (m, 2H), 7.50-7.64 (m, 2H), 7.05- 7.16 (d, 1H), 4.24-4.75 (m, 6H), 3.83-4.06 (m, 3H), 3.02- 3.18 (m, 4H) MS m/z (M + H⁺) 469.0 1188 1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[3′- (trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3- yl)piperazine MS m/z (M + H⁺) 501.0 1228 1-{1-[(3′-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 451.0 1239 1-{1-[(2′,4′-Difluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 469.0 1172 1-{1-[(2-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 451.0 1200 1-{1-[(4-Chlorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 467.0 1168 1-{1-[(6-Methoxybiphenyl-3-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 463.0 1234 1-{1-[(2-Methylbiphenyl-3-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 447.0 1240 1-{1-[(2-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 451.0 1288 1-{1-[(4-Chlorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 467.0 1265 1-{1-[(6-Methoxybiphenyl-3-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 463.0 1285 1-{1-[(2-Methylbiphenyl-3-yl)carbonyl]azetidin-3-yl}-4- (1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 447.0 1208 1-{1-[(4-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine MS m/z (M + H⁺) 451.0 1280 1-{1-[(4-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 451.0 1144 1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[5- (trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3- yl)piperazine 1H NMR (300 MHz, CD₃OD): δ 8.12 (s, 1H), 8.07 (s, 1H), 7.96 (d, 1H), 7.92 (s, 1H), 7.86 (d, 1H), 7.67-7.74 (m, 2H), 7.42-7.57 (m, 3H), 4.57-4.74 (m, 3H), 4.38-4.55 (m, 2H), 4.33 (m, 1H), 3.91-4.02 (m, 2H), 3.85 (m, 1H), 3.01-3.13 (m, 4H) MS m/z (M + H⁺) 501.0 1104 1-{1-[(5-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-2-ylcarbonyl)piperazine ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.88 (d, 1H), 7.64-7.74 (m, 3H), 7.56-7.63 (dt, 1H), 7.35-7.53 (m, 4H), 4.31-4.83 (m, 6H), 3.94-4.10 (m, 3H), 3.19-3.27 (m, 4H) MS m/z (M + H⁺) 451.0 1259 1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[5- (trifluoromethyl)biphenyl-3-yl]carbonyl}azetidin-3- yl)piperazine MS m/z (M + H⁺) 501.0 1273 1-{1-[(5-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-4-(1,3- thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 451.0 1114 1-(Isothiazol-5-ylcarbonyl)-4-(1-{[2-methyl-3′- (trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperazine ¹H NMR (400 MHz, CDCl₃): δ 8.56 (d, 1H); 7.92 (d, 1H); 7.78-7.56 (m, 5H); 7.46 (m, 1H); 4.45 (m, 1H); 4.41-4.19 (m, 3H); 3.94 (bs, 5H); 3.12 (bs, 4H); 2.5 (s, 3H) MS m/z (M + H⁺) 515.2 1138 1-(1H-Pyrrol-2-ylcarbonyl)-4-[1-({4-[5- (trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)azetidin-3- yl]piperazine MS m/z (M + H⁺) 489 1268 1-(1,3-Thiazol-5-ylcarbonyl)-4-[1-({4-[5- (trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)azetidin-3- yl]piperazine MS m/z (M + H⁺) 507.1

Example 59a

Following the procedure described above for Example 2 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1212 1-{[3-Methyl-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}- 4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 515.12 1136 1-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]-4-({4-[5- (trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)piperazine MS m/z (M + H⁺) 507.05 1260 1-{[3-Methyl-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}- 4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperazine MS m/z (M + H⁺) 515.2 1161 1-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]-4-({4-[5- (trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)piperazine MS m/z (M + H⁺) 507.1 1162 1-[1-(1H-Pyrrol-2-ylcarbonyl)azetidin-3-yl]-4-({4-[5- (trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)piperazine MS m/z (M + H⁺) 489.2

Example 60

A. Methyl 4-((4-fluorophenyl)amino)-3-nitrobenzoate, 60c

A mixture of methyl 4-fluoro-3-nitrobenzoate 60a (1 g, 5.02 mmol), 4-fluoroaniline 60b (4.34 mL, 5.02 mmol), and DIPEA (1.04 mL, 6.03 mmol) in DMF (10 mL) was stirred at room temperature for 2 h. Water was added to the mixture; the resulting solid was filtered, washed with water, and dried. The crude product 60c was used in the next reaction without purification.

B. Methyl 3-amino-4-((4-fluorophenyl)amino)benzoate, 60d

A mixture of 60c (1.4 g, 4.8 mmol) and SnCl₂.2H₂O (4.9 g, 21.7 mmol) in EtOH (50 mL) was stirred at 80° C. After 4 h, the mixture was cooled to room temperature and was slowly added to saturated aqueous NaHCO₃. The solid was filtered and washed with H₂O. The solid was triturated with EtOAc and the filtrate was concentrated. The crude product 60d was used in the next reaction without purification. MS m/z (M+H⁺) 261.1.

C. Methyl 1-(4-fluorophenyl)-1H-benzo[d]imidazole-5-carboxylate, 60e

A mixture of 60d (0.18 g, 0.693 mmol) and trimethyl orthoformate (0.7 mL, 6.39 mmol) in DMF (2 mL) was refluxed for 5 h and then cooled to room temperature. Water was added to the mixture. The resulting solid was filtered, washed, with water, and dried. The crude product 60e was used in the next reaction without purification. MS m/z (M+H⁺) 271.1.

D. 1-(4-Fluorophenyl)-1H-benzo[d]imidazole-5-carboxylic acid, 60f

To a solution of 60e (0.18 g, 0.666 mmol) in EtOH (10 mL) was added 1N aqueous NaOH (2.5 mL, 2.5 mmol). The mixture was stirred at room temperature for 4 d. The solvent was evaporated and 1N aqueous HCl was added, followed by extraction with EtOAc. The organic layer was dried over MgSO₄ and concentrated. The crude product 60f was purified by preparative reverse phase chromatography. MS m/z (M+H⁺) 257.1.

E. 1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole, Cpd 1167

To a solution of 5e (0.058 g, 0.178 mmol) and HATU (0.081 g, 0.214 mmol) in CH₂Cl₂ (3 mL) was added Et₃N (0.099 mL, 0.713 mmol). The mixture was stirred at room temperature for 30 min, and then 60f (0.050 g, 0.196 mmol) was added. The reaction mixture was stirred at room temperature overnight. Water (6 mL) was added and the mixture was extracted with EtOAc. The organic layer was dried over MgSO₄ and concentrated. The crude product Cpd 1167 was purified by preparative reverse phase chromatography. MS m/z (M+H⁺) 491.2.

Following the procedure described above for Example 60 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared.

Following the procedure described above for Example 60 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared.

Cpd Cpd Name and Data 1186 1-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 509.2 1064 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H- benzimidazole 1H NMR (300 MHz, CD₃OD): d 8.82 (s, 1H), 8.14 (s, 1H), 7.96-8.03 (m, 3H), 7.86-7.95 (m, 3H), 7.76-7.85 (m, 2H), 7.08 (d, 1H), 4.36-4.86 (m, 6H), 3.97-4.16 (m, 3H), 3.32- 3.42 (m, 4H) MS m/z (M + H⁺) 541.2 761 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-(2,2,2-trifluoroethyl)-1H-benzimidazole MS m/z (M + H⁺) 479.1 780 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-(3,3,3-trifluoropropyl)-1H-benzimidazole MS m/z (M + H⁺) 493.2 759 1-(4,4-Difluorocyclohexyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 515.2 1281 1-Phenyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 473.2 1274 1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 491.2 1270 1-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 509.1 1231 5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H- benzimidazole MS m/z (M + H⁺) 541.2 841 5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-(2,2,2-trifluoroethyl)-1H-benzimidazole MS m/z (M + H⁺) 479.1 851 5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-(3,3,3-trifluoropropyl)-1H-benzimidazole MS m/z (M + H⁺) 493.2 834 1-(4,4-Difluorocyclohexyl)-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 515.2 1207 1-Phenyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 473

Example 60a

F. Methyl 2-methyl-1-(4-fluorophenyl)-1H-benzo[d]imidazole-5-carboxylate, 60g

The title compound 60g was prepared using the method described in Example 60, substituting trimethyl orthoacetate for trimethyl orthoformate in Step C. The crude product 60g was used in the next reaction without purification. MS m/z (M+H⁺) 285.1.

G. 2-Methyl-1-(4-fluorophenyl)-1H-benzo[d]imidazole-5-carboxylate, 60h

The title compound 60h was prepared using the method described in Example 60, substituting 60g for 60e in Step D. The crude product 60h was used in the next reaction without purification. MS m/z (M+H⁺) 271.2.

H. Cpd 1227

The title compound Cpd 1227 was prepared using the method described in Example 60, substituting 60h for 60f in Step E. The crude product Cpd 1227 was purified by preparative reverse phase chromatography. MS m/z (M+H⁺) 505.2.

Following the procedure described above for Example 60a and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared.

Following the procedure described above for Example 60a and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared.

Cpd Cpd Name and Data 1229 2-Methyl-1-phenyl-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 487.2 1206 1-(3,4-Difluorophenyl)-2-methyl-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 523.2 1215 2-Methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]- 1H-benzimidazole MS m/z (M + H⁺) 555.2 789 2-Methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1-(2,2,2-trifluoroethyl)-1H- benzimidazole MS m/z (M + H⁺) 493.2 777 2-Methyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1-(3,3,3-trifluoropropyl)-1H- benzimidazole MS m/z (M + H⁺) 507.2 798 1-(4,4-Difluorocyclohexyl)-2-methyl-5-({3-[4-(1,3-thiazol- 2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 529.2 1291 1-(4-Fluorophenyl)-2-methyl-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 505.2 1296 2-Methyl-1-phenyl-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 487.2 1264 1-(3,4-Difluorophenyl)-2-methyl-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 523.2 1289 2-Methyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]- 1H-benzimidazole MS m/z (M + H⁺) 555.2 858 2-Methyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1-(2,2,2-trifluoroethyl)-1H- benzimidazole MS m/z (M + H⁺) 493.2 866 2-Methyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1-(3,3,3-trifluoropropyl)-1H- benzimidazole MS m/z (M + H⁺) 507.1 1506 1-(4,4-Difluorocyclohexyl)-2-methyl-5-({3-[4-(1,3-thiazol- 4-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- benzimidazole MS m/z (M + H⁺) 529.2 635 2-Methyl-1-phenyl-5-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-benzimidazole MS m/z (M + H⁺) 480

Example 60b

I. Methyl 1-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate, 60i

A mixture of 60d (0.20 g, 0.826 mmol) and 1,1′-carbonyldiimidazole (0.535 g, 3.3 mmol) in DMF (8 mL) was heated at 90° C. for 2 h. The solvent was removed and the residue was triturated with water (15 mL). The resulting precipitate was collected by filtration and washed several times with water. The crude product 60i was used in the next reaction without further purification. MS m/z (M+H⁺) 287.1.

J. 1-(4-Fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate, 60j

The title compound 60j was prepared using the method described in Example 60, substituting 60i for 60e in Step D. The crude product 60j was used in the next reaction without purification. MS m/z (M+H⁺) 273.1.

K. 1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3-dihydro-2H-benzimidazol-2-one, Cpd 934

The title compound Cpd 934 was prepared using the method described in Example 60, substituting 60j for 60f in Step E. The crude product Cpd 934 was purified by preparative reverse phase chromatography. MS m/z (M+H⁺) 507.1.

Following the procedure described above for Example 60b and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared.

Following the procedure described above for Example 60b and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared.

Cpd Cpd Name and Data 933 1-Phenyl-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,3-dihydro-2H-benzimidazol-2-one ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, 1H), 7.88 (d, 1H), 7.56-7.66 (m, 2H), 7.46-7.55 (m, 4H), 7.42 (dd, 1H), 7.08 (d, 1H), 4.26-4.81 (m, 6H), 3.93-4.10 (m, 3H), 3.18-3.27 (m, 4H) MS m/z (M + H⁺) 489.1 932 1-(4,4-Difluorocyclohexyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- dihydro-2H-benzimidazol-2-one MS m/z (M + H⁺) 531.0 935 1-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- dihydro-2H-benzimidazol-2-one MS m/z (M + H⁺) 525.1 936 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1,3-dihydro- 2H-benzimidazol-2-one MS m/z (M + H⁺) 557.0 937 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H- benzimidazol-2-one MS m/z (M + H⁺) 495.1 938 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-(3,3,3-trifluoropropyl)-1,3-dihydro-2H- benzimidazol-2-one MS m/z (M + H⁺) 509.1 939 1-Phenyl-5-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1,3-dihydro-2H-benzimidazol-2-one MS m/z (M + H⁺) 489.1 940 1-(4-Fluorophenyl)-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- dihydro-2H-benzimidazol-2-one MS m/z (M + H⁺) 507.1 941 1-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- dihydro-2H-benzimidazol-2-one MS m/z (M + H⁺) 525.2 942 5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1,3-dihydro- 2H-benzimidazol-2-one MS m/z (M + H⁺) 557.2 943 5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H- benzimidazol-2-one MS m/z (M + H⁺) 495.2 944 5-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-1-(3,3,3-trifluoropropyl)-1,3-dihydro-2H- benzimidazol-2-one MS m/z (M + H⁺) 509.2 945 1-(4,4-Difluorocyclohexyl)-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1,3- dihydro-2H-benzimidazol-2-one MS m/z (M + H⁺) 531.2

Example 61

A. 3-Fluoro-6-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid, 61a

A solution of 6-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid 10a (2.031 mmol, 0.50 g) in THF (8 mL) at −70° C. was treated with a 1.6 M solution of n-BuLi in hexanes (4.26 mmol, 2.66 mL). After 1 h at −70° C., N-fluorobenzenesulfonimide (2.64 mmol, 0.833 g) in THF (2 mL) was slowly added and the reaction was warmed to room temperature. After 1 h the mixture was partitioned between dilute aqueous HCl and EtOAc. The organic layer was washed with water and brine, and then concentrated. The residue was triturated with CH₂Cl₂. The off-white precipitate was filtered and collected to provide 61a.

B. 3-Fluoro-6-trifluoromethyl-benzo[b]thiophene-2-carbonyl chloride, 61b

The title compound 61b was prepared using the method described in Example 10, substituting 61a for 10a in Step A.

C. 1-(1-{[3-Fluoro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 895

The title compound Cpd 895 was prepared using the method described in Example 10, substituting 61b for 10b in Step B. MS m/z (M+H⁺) 499.

Following the procedure described above for Example 61 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 653 1-(1-{[3-Fluoro-6-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4-ylcarbonyl)piperazine MS m/z (M + H⁺) 499 509 1-(1-{[3-Fluoro-6-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 492

Example 62

A. 1-tert-Butyl 6-methyl 3-phenyl-1H-indole-1,6-dicarboxylate, 62b

A mixture of 1-tert-butyl 6-methyl 3-iodo-1H-indole-1,6-dicarboxylate 62a (5.02 mmol, 2.016 g), phenylboronic acid 1x (7.53 mmol, 0.92 g), Pd(OAc)₂ (0.402 mmol, 90 mg), Sphos 0.904 mmol, (0.37 g), and K₃PO₄ (10.1 mmol, 2.13 g) in toluene (10 mL) in sealed reaction vial was stirred at room temperature for 2 min and then heated at 90° C. under N₂ for 4 h. The reaction mixture was quenched with EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 8% EtOAc/hexanes). The desired product was collected as a light yellow solid that was washed with small amount of hexanes to obtain 62b as a white solid.

B. Methyl 3-phenyl-1H-indole-6-carboxylate TFA salt, 62c

To a solution of 1-tert-butyl 6-methyl 3-phenyl-1H-indole-1,6-dicarboxylate 62b (4.04 mmol, 1.42 g) in CH₂Cl₂ (8 mL) was added 6 mL of TFA. The resulting solution was stirred for 3 h. The mixture was then concentrated and washed with hexanes to afford 62c.

C. Methyl 1-methyl-3-phenyl-1H-indole-6-carboxylate, 62d

NaH (60% dispersion in mineral oil, 4.52 mmol, 186 mg) was added portion-wise to a solution of methyl 3-phenyl-1H-indole-6-carboxylate TFA salt 62c (2.07 mmol, 757 mg) in DMF at 0° C. and the mixture was stirred for 20 min. Methyl iodide (2.28 mmol, 0.14 mL) was added and the reaction mixture was maintained at 0° C. for 1 h. Water was then added and the reaction was extracted with EtOAc. The organics were concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give 62d.

D. 1-Methyl-3-phenyl-1H-indole-6-carboxylic acid, 62e

The title compound 62e was prepared using the method described in Example 29, substituting 62d for 29c in Step B.

E. 1-Methyl-3-phenyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole, Cpd 1132

The title compound Cpd 1132 was prepared using the method described in Example 9, substituting 62d for 9c in Step D. MS m/z (M+H⁺) 486.

Following the procedure described above for Example 62 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Following the procedure described above for Example 62 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 701 3-Iodo-1-methyl-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 536 1084 1-Methyl-6-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-3-[3-(trifluoromethyl)phenyl]- 1H-indole MS m/z (M + H⁺) 554 1148 1-Methyl-6-({3-[4-(1,3-thiazol-4-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-3-[4-(trifluoromethyl)phenyl]- 1H-indole MS m/z (M + H⁺) 554 1100 1-Methyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-3-[3-(trifluoromethyl)phenyl]- 1H-indole MS m/z (M + H⁺) 554 1347 1-Methyl-6-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-3-[4-(trifluoromethyl)phenyl]- 1H-indole MS m/z (M + H⁺) 554 1155 1-Methyl-3-phenyl-6-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 486 593 1-Methyl-6-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-3-[3-(trifluoromethyl)phenyl]-1H-indole MS m/z (M + H⁺) 547 585 1-Methyl-3-phenyl-6-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 479

Example 62a

F. 1-tert-Butyl 6-methyl 3-(3-(trifluoromethyl)phenyl)-1H-indole-1,6-dicarboxylate, 62g

The title compound 62g was prepared using the method described in Example 62, substituting 62f for 1x in Step A.

G. Methyl 3-(3-(trifluoromethyl)phenyl)-1H-indole-6-carboxylate TFA salt, 62h

The title compound 62h was prepared using the method described in Example 62, substituting 62g for 62b in Step B.

H. 3-(3-(Trifluoromethyl)phenyl)-1H-indole-6-carboxylic acid, 62i

The title compound was prepared using the method described in Example 62, substituting 62h for 62e in Step D.

E. 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-3-[3-(trifluoromethyl)phenyl]-1H-indole, Cpd 1341

The title compound Cpd 1341 was prepared using the method described in Example 9, substituting 62i for 9c in Step D. MS m/z (M+H⁺) 540.

Following the procedure described above for Example 62a and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compound was prepared:

Following the procedure described above for Example 62a and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 572 6-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-3-[3-(trifluoromethyl)phenyl]-1H-indole MS m/z (M + H⁺) 533 634 6-({3-[4-(Phenylcarbonyl)piperazin-1-yl]azetidin-1- yl}carbonyl)-3-[4-(trifluoromethyl)phenyl]-1H-indole MS m/z (M + H⁺) 533 1340 6-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-3-[4-(trifluoromethyl)phenyl]-1H-indole MS m/z (M + H⁺) 540 1344 6-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-3-[4-(trifluoromethyl)phenyl]-1H-indole MS m/z (M + H⁺) 540 1345 6-({3-[4-(1,3-Thiazol-4-ylcarbonyl)piperazin-1-yl]azetidin- 1-yl}carbonyl)-3-[3-(trifluoromethyl)phenyl]-1H-indole MS m/z (M + H⁺) 540

Example 63

A. Methyl 4-(hydroxy(4-(trifluoromethyl)phenyl)methyl)benzoate, 63c

To a solution of methyl 4-iodobenzoate 63a (8 mmol, 2.1 g) in 10 mL of dry THF was added i-propyl magnesium chloride (2M in THF, 8.4 mmol, 4.2 mL) dropwise under N₂ at −20° C. The solution was stirred for 30 min. The formed Grignard reagent in THF was then added slowly to a solution of 4-trifluoromethylbenzaldehyde (8 mmol, 1.1 mL) in THF (20 mL) at −40° C. After 20 min, the reaction mixture was allowed to warm up slowly to room temperature. The reaction was quenched with saturated aqueous NH₄Cl and extracted with EtOAc. The organic layer was concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give the 63c as white solid.

B. 4 Methyl 4-(fluoro(4-(trifluoromethyl)phenyl)methyl)benzoate, 63d

To a solution of 63c (0.97 mmol, 300 mg) in CH₂Cl₂ was added DAST (1.015 mmol, 0.133 mL) dropwise at −78° C. under N₂. The reaction was kept at −78° C. for 30 min and then quenched with aqueous NaHCO₃ solution at low temperature. Additional CH₂Cl₂ was added to the reaction and the organic solution was concentrated. The crude material was purified flash column chromatography (silica gel, 10% EtOAc/hexanes) to give 63d.

C. 4-(Fluoro(4-(trifluoromethyl)phenyl)methyl)benzoic acid, 63e

The title compound was prepared using the method described in Example 29, substituting 63d for 29c in Step B.

D. 1-[1-[(4-{Fluoro[4-(trifluoromethyl)phenyl]methyl]phenyl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 982

The title compound Cpd 982 was prepared using the method described in Example 9, substituting 63e for 9c in Step D. MS m/z (M+H⁺) 533.

Example 64

A. Methyl 4-(2-phenyl-1,3-dithiolan-2-yl)benzoate, 64b

Methyl 4-benzoylbenzoate 64a (2.08 mmol, 0.50 g) and BF₃. (OAc)₂ (5.2 mmol, 0.73 mL) were dissolved in dry CH₂Cl₂ under N₂. Ethane-1,2-dithiol (3.95 mmol, 0.333 mL) was added and the solution was stirred overnight. The reaction mixture was partitioned between CH₂Cl₂ and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 10% EtOAc/hexanes) to afford compound 64b.

B. Methyl 4-(difluoro(phenyl)methyl)benzoate, 64c

Selectfluor (1.07 mmol, 381 mg) and HF-pyridine reagent (1.5 mL, HF: Pyridine=70:30 wt %) were dissolved in CH₂Cl₂ (4 mL) in a polyethylene bottle and cooled to 0° C. A solution of 64b (0.512 mmol, 162 mg) in CH₂Cl₂ (2 mL) was slowly added and the mixture was stirred for 45 min at room temperature. When TLC indicated the consumption of all 64b, the reaction was diluted with CH₂Cl₂. The combined organics were dried over anhydrous Na₂SO₄ and concentrated. The crude product was purified by flash column chromatography (silica gel, 5% EtOAc/hexanes) to afford compound 64c as a clear oil.

C. 4-(Difluoro(phenyl)methyl)benzoic acid, 64d

The title compound 64d was prepared using the method described in Example 29, substituting 64c for 29c in Step B.

D. 1-[1-({4-[Difluoro(phenyl)methyl]phenyl}carbonyl)azetidin-3-yl]-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 986

The title compound Cpd 986 was prepared using the method described in Example 9, substituting 64d for 9c in Step D. MS m/z (M+H⁺) 483.

Example 65

A. Methyl 3-cyclopropyl-6-fluorobenzo[b]thiophene-2-carboxylate, 65c

A mixture of methyl 3-chloro-6-fluorobenzo[b]thiophene-2-carboxylate 65a (0.613 mmol, 150 mg), cyclopropylboronic acid 65b (0.92 mmol, 79 mg), Pd(OAc)₂ (0.09 mmol, 20 mg), SPhos (0.215 mmol, 88 mg), and K₃PO₄ (1.23 mmol, 0.26 g) in toluene (2 mL) was heated to 100° C. for 3 h in a sealed reaction vessel. The reaction was diluted with EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 10% EtOAc/hexanes) to give compound 65c.

B. 3-Cyclopropyl-6-fluoro-benzo[b]thiophene-2-carboxylic acid, 65d

The title compound 65d was prepared using the method described in Example 29, substituting 65c for 29c in Step B.

C. 3-Cyclopropyl-6-fluoro-benzo[b]thiophene-2-carbonyl chloride, 65e

The title compound 65e was prepared using the method described in Example 10, substituting 65d for 10a in Step A.

D. 1-{1-[(3-Cyclopropyl-6-fluoro-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 714

The title compound Cpd 714 was prepared using the method described in Example 10, substituting 65e for 10b in Step B. MS m/z (M+H⁺) 471.

Following the procedure described above for Example 65 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following intermediate compound was prepared:

Following the procedure described above for Example 65 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 695 1-{1-[(3-Cyclobutyl-6-fluoro-1-benzothiophen-2- yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 485 528 1-{1-[(3-Cyclopropyl-6-fluoro-1-benzothiophen-2- yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 464 513 1-{1-[(3-Cyclobutyl-6-fluoro-1-benzothiophen-2- yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 478 1346 1-{1-[(3-Methyl-5-phenyl-1-benzothiophen-2- yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-2- ylcarbonyl)piperazine NMR (CDCl₃) δ: 7.96 (d, J = 1.2 Hz, 1H), 7.84-7.93 (m, 2H), 7.62-7.74 (m, 3H), 7.55 (d, J = 3.2 Hz, 1H), 7.49 (m, 2H), 7.34-7.44 (m, 1H), 4.12-4.47 (m, 6H), 3.87 (m, 2H), 3.19-3.35 (m, 1H), 2.69 (s, 3H), 2.50 (m, 4H) MS m/z (M + H⁺) 503 1058 1-{1-[(3-Methyl-5-phenyl-1-benzothiophen-2- yl)carbonyl]azetidin-3-yl}-4-(1,3-thiazol-4- ylcarbonyl)piperazine; MS m/z (M + H+) 503 691 1-(1-{[5-Methyl-3-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine; MS m/z (M + H+) 495 737 1-(1-{[5-Methyl-3-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine; MS m/z (M + H+) 495 707 1-(1-{[6-Methyl-3-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine; MS m/z (M + H+) 495 712 1-(1-{[6-Methyl-3-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine; MS m/z (M + H+) 495 1098 1-(1-{[6-Phenyl-3-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine; MS m/z (M + H+) 557 1095 1-(1-{[6-Phenyl-3-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine; MS m/z (M + H+) 557 570 1-{1-[(3-Methyl-5-phenyl-1-benzothiophen-2- yl)carbonyl]azetidin-3-yl}-4-(phenylcarbonyl)piperazine; MS m/z (M + H+) 496 510 1-(1-{[6-Methyl-3-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine; MS m/z (M + H+) 488

Example 66

A. Methyl 4-thiomorpholinoquinazoline-7-carboxylate, 66c

A solution of methyl 4-chloroquinazoline-7-carboxylate 66a (1.01 mmol, 225 mg) and thiomorpholine 66b (2.02 mmol, 208 mg) in MeOH (1.6 mL) was refluxed overnight. Compound 66c (30 mg) was isolated after purification.

B. 4-Thiomorpholinoquinazoline-7-carboxylic acid, 66d

The title compound 66d was prepared using the method described in Example 29, substituting 66c for 29c in Step B.

C. 7-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-4-thiomorpholin-4-ylquinazoline, Cpd 951

The title compound Cpd 951 was prepared using the method described in Example 9, substituting 66d for 9c in Step D. MS m/z (M+H⁺) 510.

Example 67

A. 1-(5-Chloro-2-fluoro-phenyl)-2,2,2-trifluoro-ethanone, 67c

To a solution of LDA (2.0 M in THF/heptane/ethylbenzene, 25.3 mmol, 12.6 mL) in dry THF was slowly added 1-fluoro-4-chloro-benzene 67a (23.0 mmol, 2.45 mL) at −78° C. The mixture was stirred for 1 h at −78° C. and ethyl trifluoroacetate 67b (25.3 mmol, 3.02 mL) was added. The reaction mixture was allowed to warm to room temperature overnight and was quenched with saturated aqueous NH₄Cl solution. The mixture was extracted with EtOAc. The organic extracts were concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give a mixture of the compound 67c along with a regio-isomeric by-product, 1-(5-fluoro-2-chloro-phenyl)-2,2,2-trifluoro-ethanone, in a ratio of 5:1 (67c is the major product).

B. Methyl 5-chloro-3-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 67e

A solution of compound 67c (6.62 mmol, 1.5 g), methyl 2-mercaptoacetate 67d (6.62 mmol, 0.6 mL), and Et₃N (8.6 mmol, 1.2 mL) in acetonitrile (12 mL) was heated at 75° C. for 4 h. The reaction was diluted with EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 10% EtOAc/hexanes) to provide the compound 67e.

C. 5-Chloro-3-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid, 67f

The title compound 67f was prepared using the method described in Example 29, substituting 67e for 29c in Step B.

D. 5-Chloro-3-trifluoromethyl-benzo[b]thiophene-2-carbonyl chloride, 67g

The title compound 65e was prepared using the method described in Example 10, substituting 67f for 10a in Step A.

E. 1-(1-{[5-Chloro-3-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine

The title compound Cpd 896 was prepared using the method described in Example 10, substituting 67g for 10b in Step B. MS m/z (M+H⁺) 515.

Following the procedure described above for Example 67 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 673 1-(1-{[5-Chloro-3-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 515 506 1-(1-{[5-Chloro-3-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 508

Example 67a

F. 1-(4-Chloro-2-fluoro-phenyl)-2,2,2-trifluoro-ethanone, 67i

To a solution of n-BuLi (1.6 M in hexanes, 4.68 mmol, 2.93 mL) in dry THF was slowly added 4-chloro-2-fluoro-1-iodo-benzene 67h (3.9 mmol, 1.0 g) at −78° C. under N₂. The mixture was stirred for 1 h at −78° C. and ethyl trifluoroacetate 67b (0.51 mL, 4.29 mmol) was added. The reaction was allowed to warm to room temperature overnight and was quenched with saturated aqueous NH₄Cl solution. The mixture was extracted with EtOAc. The organic extracts were concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give compound 67i.

G. Methyl 6-chloro-3-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 67j

The title compound 67j was prepared using a similar method described in Example 67, substituting 67i for 67c in Step B.

Following the procedure described above for Example 67, Steps C-E, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 664 1-(1-{[6-Chloro-3-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine MS m/z (M + H⁺) 515 699 1-(1-{[6-Chloro-3-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 515 512 1-(1-{[6-Chloro-3-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4- (phenylcarbonyl)piperazine MS m/z (M + H⁺) 508

Example 67b

H. Methyl 6-chloro-3-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 67l

The title compound 671 was prepared using a similar method described in Example 67, substituting 67k for 67c, substituting NaH for Et₃N, and substituting THF and DMSO for CH₃CN in Step B.

Following the procedure described above for Example 67, Steps C-E, and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 692 1-(Isothiazol-5-ylcarbonyl)-4-(1-{[3-methyl-6- (trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)piperazine ¹H NMR (CDCl₃): δ 8.41 (ar, 1H); 8.22 (ar, 1H); 7.98 (m, 1H); 7.65 (m, 1H); 7.48, (m, 1H); 3.83 (bm, 5H); 3.01 (bm, 4H); 2.5 (s, 3H) MS m/z (M + H⁺) 477.0 505 1-(1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(phenylcarbonyl)piperazine MS m/z (M + H⁺) 488 899 1-(1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2- ylcarbonyl)piperazine ¹H NMR (CDCl₃, 400 MHz): δ 8.11 (s, 1 H), 7.83-7.95 (m, 2 H), 7.65 (d, J = 8.6 Hz, 1 H), 7.55 (d, J = 3.1 Hz, 1 H), 3.99-4.67 (m, 6 H), 3.87 (br. s., 2 H), 3.16-3.41 (m, 1 H), 2.66 (s, 3 H), 2.50 (br. s., 4 H). MS m/z (M + H⁺) 495 674 1-(1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine ¹H NMR (CDCl₃, 400 MHz): δ 8.79 (s, 1 H), 8.10 (s, 1 H), 8.03 (s, 1 H), 7.89 (d, J = 8 Hz, 1 H), 7.65 (d, J = 8 Hz, 1 H), 3.80-4.40 (m, 8 H), 3.28 (m, 1 H), 2.66 (s, 3 H), 2.49 (br. s., 4 H). MS m/z (M + H⁺) 495 657 1-(1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}azetidin-3-yl)-4-(1H-pyrrol-2- ylcarbonyl)piperazine ¹H NMR (400 MHz, CDCl₃): δ 8.33 (d, 1H); 8.09 (d, 1H); 7.72 (d, 1H); 6.95 (s, 1H); 6.67 (s, 1H); 6.23 (dd, 1H); 4.59 (bm, 3H); 4.26 (m, 1H); 3.40 (m, 3H); 2.68 (s, 3H) MS m/z (M + H⁺) 477.1

Example 68

A. Methyl 3-Hydroxy-6-trifluoromethylbenzo[b]thiophene-2-carboxylate, 68b

LiOH (4.5 mmol, 0.11 g) was added to a solution of methyl 2-fluoro-4-trifluoromethylbenzoate 68a (2.25 mmol, 0.50 g) and methyl 2-mercaptoacetate 67d (2.25 mmol, 0.21 mL) in DMF (3 mL) at 0° C. The mixture was stirred at 0° C. for 30 min and then warmed to room temperature and stirred for 1 h. Water was added and the resulting solution was acidified with 1N aqueous HCl. The precipitates were filtered, washed with water, and dried to give compound 68b.

B. Methyl 3-methoxy-6-trifluoromethylbenzo[b]thiophene-2-carboxylate, 68c

A mixture of compound 68b (0.543 mmol, 150 mg), dimethyl sulfate (0.608 mmol, 0.058 mL), and sodium bicarbonate (0.57 mmol, 48 mg) in acetone was heated at reflux overnight. The reaction mixture was cooled and filtered. The filtrate was concentrated and the residue was partitioned between EtOAc and water. The organic solution was concentrated and purified by flash column chromatography (silica gel, 10% EtOAc/hexanes) to give compound 68c.

C. 3-Methoxy-6-trifluoromethylbenzo[b]thiophene-2-carboxylic acid, 68d

The title compound 68d was prepared using the method described in Example 29, substituting 68c for 29c in Step B.

D. 3-Methoxy-6-trifluoromethylbenzo[b]thiophene-2-carbonyl chloride, 68e

The title compound 68e was prepared using the method described in Example 10, substituting 68d for 10a in Step A.

E. 1-(1-{[3-Methoxy-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-2-ylcarbonyl)piperazine, Cpd 649

The title compound Cpd 649 was prepared using the method described in Example 10, substituting 68e for 10b in Step B. ¹H NMR (CDCl₃): δ 8.05 (s, 1H), 7.83-7.96 (m, 2H), 7.62 (dd, J=8.4, 1.1 Hz, 1H), 7.55 (d, J=3.2 Hz, 1H), 4.55-4.45 (m, 2H), 4.24-4.37 (m, 2H), 4.11-4.24 (m, 2H), 4.07 (s, 3H), 3.88 (m, 2H), 3.29 (m, 1H), 2.50 (m, 4H). MS m/z (M+H⁺) 511.

Following the procedure described above for Example 68 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 700 1-(1-{[3-Methoxy-6-(trifluoromethyl)-1-benzothiophen- 2-yl]carbonyl}azetidin-3-yl)-4-(1,3-thiazol-4- ylcarbonyl)piperazine MS m/z (M + H⁺) 511

Example 68a

Following the procedure described above for Example 2 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 705 1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}-4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3- yl]piperazine MS m/z (M + H⁺) 495.1 704 1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2- yl]carbonyl}-4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3- yl]piperazine MS m/z (M + H⁺) 495.1

Example 69

A. Methyl 3-fluoro-1H-indole-6-carboxylate, 69a

A solution of methyl 1H-indole-6-carboxylate 1j (11.4 mmol, 2.0 g) and N-fluoro-2,4,6-trimethylpyridinium triflate (14.8 mmol, 4.3 g) in MeOH (100 mL) was heated at reflux for 18 h. The reaction mixture was concentrated and purified by flash column chromatography (silica gel, 15-20% EtOAc/hexanes) to give compound 69a as an off-white solid.

B. Methyl 3-fluoro-1-(4-fluorophenyl)-1H-indole-6-carboxylate, 69c

Compound 69a (0.264 mmol, 51 mg), CuI (0.0264 mmol, 5 mg) and K₃PO₄ (0.66 mmol, 40 mg) were combined in a sealed reaction tube and the vial was back-flushed with N₂. 4-fluoro-iodobenzene 69b (0.264 mmol, 0.0394 mL) and N,N′-dimethylcyclohexane-1,2-diamine (0.0792 mmol, 0.0125 mL) were added via sringe, followed by toluene. The reaction mixture was heated at 95° C. for 6 h. The reaction was diluted with EtOAc and water. The reaction mixture was concentrated and purified by flash column chromatography (silica gel, 20% EtOAc/hexanes) to give compound 69c.

C. 3-Fluoro-1-(4-fluorophenyl)-1H-indole-6-carboxylic acid, 69d

The title compound 69d was prepared using the method described in Example 29, substituting 69c for 29c in Step B.

D. 3-Fluoro-1-(4-fluorophenyl)-5-({3-[4-(phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole, Cpd 574

The title compound Cpd 574 was prepared using the method described in Example 9, substituting 69d for 9c and substituting 2c for 5e in Step D. MS m/z (M+H⁺) 501.

Following the procedure described above for Example 69, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 589 3-Fluoro-1-phenyl-5-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 490

Example 70

A. Methyl 4-fluoro-1-triisopropylsilanyl-1H-indole-5-carboxylate, 70b

To a solution of 4-fluoro-1-triisopropylsilanyl-1H-indole-5-carboxylic acid 70a (prepared using a procedure described in Eur. J. Org. Chem. 2006, 2956) (8.08 mmol, 2.71 g) in dry CH₂Cl₂ (20 mL) was added oxalyl chloride (9.69 mmol, 0.82 mL) followed by DMF (0.81 mmol, 0.063 mL). The reaction was stirred at rt for 30 min and then concentrated. The residue was dissolved in CH₂Cl₂ (20 mL) and cooled to 0° C. Et₃N (40.4 mmol, 5.6 mL) was added, followed by slow addition of MeOH. The reaction mixture was stirred at 0° C. for 30 min and concentrated. The residue was partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 5% EtOAc/hexanes) to give compound 70b.

B. Methyl 4-fluoro-1H-indole-5-carboxylate, 70c

TBAF (1M solution in THF, 15.8 mmol, 15.8 mL) was added to a solution of compound 70b (7.9 mmol, 2.76 g) in THF at 0° C. After 10 min at room temperature, the reaction was diluted with EtOAc and washed with brine, saturated NaHCO₃, and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 35% EtOAc/hexanes) to afford compound 70c.

C. Methyl 4-fluoro-1-(4-fluorophenyl)-1H-indole-5-carboxylate, 70d

The title compound 70d was prepared using the method described in Example 69, substituting 70c for 69a in Step B.

D. 4-Fluoro-1-(4-fluoro-phenyl)-1H-indole-5-carboxylic acid, 70e

The title compound 70e was prepared using the method described in Example 29, substituting 70d for 29c in Step B.

E. 4-Fluoro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole, Cpd 1348

The title compound Cpd 1348 was prepared using the method described in Example 9, substituting 70e for 9c in Step D. ¹H NMR (CDCl₃): δ 7.87 (d, J=3.2 Hz, 1H), 7.54 (d, J=3.2 Hz, 1H), 7.36-7.47 (m, 3H), 7.30 (d, J=3.2 Hz, 1H), 7.19-7.27 (m, 3H), 6.81 (d, J=3.2 Hz, 1H), 4.52-4.43 (m, 2H), 4.28 (dd, J=9.9, 7.7 Hz, 1H), 4.16-4.24 (m, 1H), 4.05-4.16 (m, 2H), 3.75-3.95 (m, 2H), 3.27 (m, 1H), 2.38-2.58 (m, 4H). MS m/z (M+H⁺) 508.

Following the procedure described above for Example 70, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compound was prepared:

Following the procedure described above for Example 70 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1069 6-Fluoro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 508 1349 6-Fluoro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 508 631 6-Fluoro-1-(4-fluorophenyl)-5-({3-[4- (phenylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)- 1H-indole MS m/z (M + H⁺) 501 632 4-Fluoro-1-phenyl-5-({3-[4-(phenylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 501

Example 70a

F. 7-Fluoro-1H-indole-5-carboxylic acid, 70h

To a solution of 5-bromo-7-fluoroindole 70f (1.71 mmol, 365 mg) in THF at −60° C. was added n-BuLi (1.6 M solution in hexanes, 5.2 mmol, 3.2 mL). The solution was kept at −60° C. for 4 h and was then poured onto an excess of freshly crushed dry ice. Water was added and the mixture was acidified to pH=4. The organic phase was concentrated and the residue was purified by flash column chromatography (silica gel, 35% EtOAc/hexanes) to give compound 70h.

Following the procedure described above for Example 70 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compound was prepared:

Following the procedure described above for Example 70 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1350 7-Fluoro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole ¹H NMR (CDCl₃): δ 7.88 (d, J = 3.2 Hz, 1H), 7.76 (d, J = 1.2 Hz, 1H), 7.55 (d, J = 3.2 Hz, 1H), 7.42 (m, 2H), 7.22-7.31 (m, 2H), 7.12-7.22 (m, 2H), 6.69-6.81 (m, 1H), 4.53-4.27 (m, 5H), 4.12 (m, 1H), 3.89-3.83 (m, 2H), 3.26 (m, 1H), 2.50 (m, 4H) MS m/z (M + H⁺) 508 1111 7-Fluoro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 508

Example 70b

G. Methyl 7-methyl-1H-indole-5-carboxylate, 70k

The titled compound was prepared using the method described in Example 65, substituting 70i for 65a and substituting 70j for 65b in Step A.

Following the procedure described above for Example 70 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compound was prepared:

Following the procedure described above for Example 70 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1355 1-(4-Fluorophenyl)-7-methyl-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole ¹H NMR (CDCl₃): δ 7.88 (d, J = 2.4 Hz, 1H), 7.81 (s, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.36 (m, 2H), 7.28 (S, 1H), 7.10-7.21 (m, 3H), 6.67 (d, J = 2.4 Hz, 1H), 4.55-4.26 (m, 5H), 4.12 (m, 1H), 3.89 (m, 2H), 3.25 (m, 1H), 2.50 (m, 4H), 2.02 (s, 3H) MS m/z (M + H⁺) 504 1076 1-(4-Fluorophenyl)-7-methyl-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 504

Example 70c

H. Methyl 4-amino-2-chloro-benzoate, 70m

Acetyl chloride (35.2 mmol, 2.5 mL) was added dropwise to a stirring solution of 4-amino-2-chloro-benzoic acid 70l (12.9 mmol, 2.22 g) in methanol (50 mL). The mixture was heated at reflux for 18 h, cooled, and concentrated under vacuum. The residue was taken up in EtOAc, washed with saturated aqueous NaHCO₃ and brine, dried, and concentrated under vacuum. The crude product was purified by flash column chromatography (silica gel, 30% EtOAc/hexanes) to give compound 70m.

I. Methyl 4-amino-2-chloro-5-iodo-benzoate, 70n

To a suspension of compound 70m (1.18 g, 6.38 mmol) and CaCO₃ (12.8 mmol, 1.28 g) in MeOH (13 mL) was added a solution of iodine monchloride (6.70 mmol, 1.09 g) in CH₂Cl₂ (6 mL) dropwise at room temperature. The resulting reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated and then partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 20-25% EtOAc/hexanes) to provide methyl 4-amino-2-chloro-5-iodo-benzoate 70n as major the product and methyl 4-amino-2-chloro-3-iodo-benzoate 70o as the minor product.

J. Methyl 4-amino-2-chloro-5-((trimethylsilyl)ethynyl)benzoate, 70p

To a mixture of compound 70n (0.642 mmol, 200 mg), CuI (0.064 mmol, 12.2 mg) and Pd(PPh₃)₂Cl₂ (0.064 mmol, 45 mg) in THF (2 mL) was added ethynyltrimethylsilane (0.963 mmol, 95 mg) followed by Et₃N (7.19 mmol, 1 mL) under N₂. The reaction mixture was stirred at room temperature for 1.5 h and then partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give compound 70p.

K. Methyl 6-chloro-1H-indole-5-carboxylate, 70q

A mixture of compound 70p (0.532 mmol, 150 mg) and CuI (0.32 mmol, 60 mg) in DMF (1.5 mL) was heated at 110° C. for 5 h and them cooled to room temperature. The reaction was quenched with water and extracted with EtOAc. The organic layer was concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give compound 70q.

Following the procedure described above for Example 70c and Example 70 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Following the procedure described above for Example 70 and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1416 6-Chloro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 525 1415 1-(4-Fluorophenyl)-6-methyl-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole MS m/z (M + H⁺) 504 1414 4-Chloro-1-(4-fluorophenyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indole ¹H NMR (CDCl₃): δ 7.87 (d, J = 3.2 Hz, 1H), 7.54 (d, J = 3.2 Hz, 1H), 7.40-7.46 (m, 2H), 7.34-7.39 (m, 2H), 7.19-7.29 (m, 3H), 6.83 (d, J = 3.2 Hz, 1H), 4.52 (m, 1H), 4.35-4.48 (m, 1H), 4.30 (dd, J = 9.9, 7.5 Hz, 1H), 4.08-4.18 (m, 1H), 3.75-4.05 (m, 4H), 3.23-3.33 (m, 1H), 2.37-2.57 (m, 4H) MS m/z (M + H⁺) 525.

Example 71

A. Methyl 1-(2,2-difluoroethyl)-1H-indole-5-carboxylate, 71b

To a suspension of NaH (60% dispersion in mineral oil, 1.48 mmol, 59 mg) in DMF (2 mL) was slowly added a solution of 1H-indole-5-carboxylic acid methyl ester 1j (1.14 mmol, 200 mg) in DMF (1 mL) at 0° C. The resulting solution was stirred at 0° C. for 20 min and 1,1-difluoro-2-iodoethane 71a (1.37 mmol, 263 mg) was added. The reaction was warmed to room temperature and stirred for 2 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was concentrated and purified by flash column chromatography (silica gel, 20% EtOAc/hexanes) to afford compound 71b.

B. 1-(2,2-Difluoroethyl)-1H-indole-5-carboxylic acid, 71c

The title compound 71c was prepared using the method described in Example 29, substituting 71b for 29c in Step B.

C. 1-(2,2-Difluoroethyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole, Cpd 711

The title compound Cpd 711 was prepared using the method described in Example 9, substituting 71c for 9c in Step D. ¹H NMR (CDCl₃): δ 7.94 (s, 1H), 7.88 (d, J=2.9 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.54 (d, J=2.9 Hz, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.17 (d, J=2.9 Hz, 1H), 6.63 (d, J=2.9 Hz, 1H), 6.01 (m, 1H), 4.51-4.24 (m, 7H), 4.12 (m, 1H), 3.85 (m, 2H), 3.24 (m, 1H), 2.49 (m, 4H). MS m/z (M+H⁺) 460.

Following the procedure described above for Example 71, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Following the procedure described above for Example 71, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 813 1-(2,2-Difluoroethyl)-5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 460 1031 N-Methyl-N-phenyl-2-[5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol- 1-yl]acetamide MS m/z (M + H⁺) 543 1032 N-Methyl-N-phenyl-2-[5-({3-[4-(1,3-thiazol-4- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indol- 1-yl]acetamide MS m/z (M + H⁺) 543 1035 1-(2-Oxo-2-pyrrolidin-1-ylethyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 507 1046 1-(Pyridin-4-ylmethyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 487 1047 1-(Pyridin-4-ylmethyl)-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 487 1048 1-(Pyridin-3-ylmethyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indole MS m/z (M + H⁺) 487

Example 72

A. Ethyl 1-(4-fluorobenzyl)-1H-indazole-5-carboxylate, 72c, and ethyl 2-(4-fluorobenzyl)-2H-indazole-5-carboxylate, 72d

Ethyl 1H-indazole-5-carboxylate 72a (0.79 mmol, 150 mg) and Cs₂CO₃ (0.96 mmol, 312 mg) were combined in 2 mL of DMF, producing a clear, red-brown solution. Neat 1-(bromomethyl)-4-fluorobenzene 72b (0.87 mmol, 0.11 mL) was added dropwise and the mixture was stirred at room temperature overnight. EtOAc was added and the organic layer was washed with water and brine. The organic solution was dried over Na₂SO₄ and concentrated to give 260 mg of orange solid. The crude product was purified by flash column chromatography (silica gel, 15-50% EtOAc/heptanes) to give 133 mg (57%) of compound 72c as an orange solid and 67 mg (28%) of compound 72d as a white solid.

Compound 72c:

¹H NMR (400 MHz, CDCl₃): δ 1.41 (t, J=7.1 Hz, 3H), 4.40 (q, J=7.1 Hz, 2H), 5.58 (s, 2H), 6.99 (t, J=8.7 Hz, 2H), 7.19 (dd, J=8.8, 5.3 Hz, 2H), 7.36 (dt, J=8.9, 0.8 Hz, 1H), 8.04 (dd, J=8.9, 1.5 Hz, 1H), 8.15 (d, J=0.9 Hz, 1H), 8.53 (dd, J=1.5, 0.8 Hz, 1H). MS m/z (M+H⁺) 299.1.

Compound 72d:

¹H NMR (400 MHz, CDCl₃): δ 1.41 (t, J=7.1 Hz, 3H), 4.39 (q, J=7.1 Hz, 2H), 5.59 (s, 2H), 7.07 (t, J=8.7 Hz, 2H), 7.27-7.34 (m, 2H), 7.72 (dt, J=9.1, 0.9 Hz, 1H), 7.92 (dd, J=9.1, 1.6 Hz, 1H), 8.02-8.06 (m, 1H), 8.48 (dd, J=1.5, 0.9 Hz, 1H). MS m/z (M+H⁺) 299.1.

B. 1-(4-Fluorobenzyl)-1H-indazole-5-carboxylate, 72e

To a stirring solution of compound 72c (0.43 mmol, 128 mg) in 2.5 mL of THF and 0.5 mL of MeOH was added 3N aqueous NaOH (2.62 mmol, 0.87 mL) and 0.5 mL of water. After stirring at room temperature overnight, the mixture was concentrated under vacuum. The yellow residue was dissolved in 10 mL of water and acidified to pH 2-3 with aqueous HCl. The resulting precipitate was vacuum-filtered through a paper disc and washed with water. The remaining material was pumped at high vacuum to give 108 mg (93%) of compound 72e as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 1.41 (t, J=7.1 Hz, 3H), 4.39 (q, J=7.1 Hz, 2H), 5.59 (s, 2H), 7.07 (t, J=8.7 Hz, 2H), 7.27-7.34 (m, 2H), 7.72 (dt, J=9.1, 0.9 Hz, 1H), 7.92 (dd, J=9.1, 1.6 Hz, 1H), 8.02-8.06 (m, 1H), 8.48 (dd, J=1.5, 0.9 Hz, 1H). MS m/z (M+H⁺) 271.2.

C. 1-(4-Fluorobenzyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indazole, Cpd 1029

The title compound Cpd 1029 was prepared using the method described in Example 9, substituting 72e for 9c and substituting HBTU for HATU in Step D. ¹H NMR (400 MHz, CDCl₃): δ 1.41 (t, J=7.1 Hz, 3H), 4.39 (q, J=7.1 Hz, 2H), 5.59 (s, 2H), 7.07 (t, J=8.7 Hz, 2H), 7.27-7.34 (m, 2H), 7.72 (dt, J=9.1, 0.9 Hz, 1H), 7.92 (dd, J=9.1, 1.6 Hz, 1H), 8.02-8.06 (m, 1H), 8.48 (dd, J=1.5, 0.9 Hz, 1H). MS m/z (M+H⁺) 505.2.

Following the procedure described above for Example 72, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following intermediate compounds were prepared:

Following the procedure described above for Example 72, and substituting the appropriate reagents, starting materials, and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd Cpd Name and Data 1030 2-(4-Fluorobenzyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2H- indazole ¹H NMR (400 MHz, CD₃OD): δ 3.19-3.30 (m, 4 H), 4.05 (d, J = 5.6 Hz, 3 H), 4.25-4.88 (m, 6 H), 5.66 (s, 2 H), 7.09 (t, J = 8.4 Hz, 2 H), 7.33-7.43 (m, 2 H), 7.57 (d, J = 9.0 Hz, 1 H), 7.69 (d, J = 9.0 Hz, 1 H), 7.88 (m, J = 2.9 Hz, 1 H), 7.97 (d, J = 2.7 Hz, 1 H), 8.12 (s, 1 H), 8.49 (s, 1 H) MS m/z (M + H⁺) 505.2 1036 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)benzyl]- 1H-indazole ¹H NMR (400 MHz, CD₃OD): δ 3.24 (br. s., 4 H), 3.89-4.12 (m, 3 H), 4.25-4.85 (m, 6 H), 5.78 (s, 2 H), 7.37 (m, J = 8.1 Hz, 2 H), 7.60 (m, J = 8.1 Hz, 2 H), 7.66 (d, J = 8.8 Hz, 1 H), 7.72 (dd, J = 8.8, 1.5 Hz, 1 H), 7.88 (d, J = 3.0 Hz, 1 H), 7.97 (d, J = 3.3 Hz, 1 H), 8.18 (s, 1 H), 8.23 (s, 1 H) MS m/z (M + H⁺) 555.2 1037 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-2-[4-(trifluoromethyl)benzyl]- 2H-indazole ¹H NMR (400 MHz, CD₃OD): δ 3.18-3.41 (m, 4 H), 3.92-4.18 (m, 3 H), 4.27-4.86 (m, 6 H), 5.79 (s, 2 H), 7.47 (d, J = 8.1 Hz, 2 H), 7.58 (dd, J = 9.1, 1.5 Hz, 1 H), 7.66 (d, J = 8.1 Hz, 2 H), 7.70 (d, 1 H), 7.88 (d, J = 3.0 Hz, 1 H), 7.97 (d, J = 3.0 Hz, 1 H), 8.14 (s, 1 H), 8.56 (s, 1 H) MS m/z (M + H⁺) 555.2 1038 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-1-[3-(trifluoromethyl)benzyl]- 1H-indazole ¹H NMR (400 MHz, CD₃OD): δ 3.25 (br. s., 4 H), 3.89-4.13 (m, 3 H), 4.22-4.82 (m, 6 H), 5.78 (s, 2 H), 7.40-7.54 (m, 3 H), 7.58 (m, J = 7.3 Hz, 1 H), 7.69 (m, J = 8.6 Hz, 1 H), 7.73 (d, J = 8.8 Hz, 1 H), 7.88 (d, J = 3.3 Hz, 1 H), 7.97 (d, J = 3.3 Hz, 1 H), 8.18 (s, 1 H), 8.24 (s, 1 H) MS m/z (M + H⁺) 555.2 1039 5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1- yl]azetidin-1-yl}carbonyl)-2-[3-(trifluoromethyl)benzyl]- 2H-indazole ¹H NMR (400 MHz, CD₃OD): δ 3.30 (br. s., 4 H), 4.04 (d, J = 6.8 Hz, 3 H), 4.29-4.84 (m, 6 H), 5.78 (s, 2 H), 7.58 (t, J = 7.1 Hz, 3 H), 7.64 (br. s., 2 H), 7.70 (d, J = 9.1 Hz, 1 H), 7.88 (d, J = 3.0 Hz, 1 H), 7.97 (d, J = 3.0 Hz, 1 H), 8.14 (s, 1 H), 8.56 (s, 1 H) MS m/z (M + H⁺) 555.2 1411 1-(1-Phenylethyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indazole ¹H NMR (400 MHz, acetone-d₆): δ 2.01 (d, J = 7.1 Hz, 3 H), 3.35 (br. s., 4 H), 4.07 (br. s., 2 H), 4.11-4.19 (m, 1 H), 4.25-4.53 (m, 2 H), 6 4.60 (br. s., 1 H), 4.68-4.96 (m, 3 H), 6.07 (q, J = 7.1 Hz, 1 H), 7.24 (d, J = 7.1 Hz, 1 H), 7.30 (t, J = 7.3 Hz, 2 H), 7.33-7.39 (m, 2 H), 7.58-7.68 (m, 2 H), 7.92 (d, J = 3.3 Hz, 1 H), 7.98 (d, J = 3.0 Hz, 1 H), 8.12 (s, 1 H), 8.18 (s, 1 H) MS m/z (M + H⁺) 501.1 1040 2-(1-Phenylethyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2H- indazole ¹H NMR (400 MHz, CD₃OD): δ 2.04 (d, J = 7.1 Hz, 3 H), 3.20 (br. s., 4 H), 3.91-4.05 (m, 3 H), 4.25-4.63 (m, 4 H), 4.72 (br. s., 2 4 H), 5.94 (q, J = 6.9 Hz, 1 H), 7.25-7.39 (m, 5 H), 7.57 (dd, J = 9.0, 1.4 Hz, 1 H), 7.69 (d, J = 9.1 Hz, 1 H), 7.88 (d, J = 3.0 Hz, 1 H), 7.97 (d, J = 3.3 Hz, 1 H), 8.12 (s, 1 H), 8.51 (s, 1 H) MS m/z (M + H⁺) 501.3 1043 1-(4-Fluorobenzyl)-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- pyrrolo[2,3-b]pyridine ¹H NMR (400 MHz, CDCl₃): δ 3.49 (br. s., 4 H), 4.12 (br. s., 2 H), 4.23-4.33 (m, 1 H), 4.34-5.17 (m, 6 H), 5.56 (s, 2 H), 6.61 (d, J = 3.5 Hz, 1 H), 7.08 (t, J = 8.7 Hz, 2 H), 7.38 (dd, J = 8.6, 5.6 Hz, 2 H), 7.63 (d, J = 3.5 Hz, 1 H), 7.93 (d, J = 3.3 Hz, 1 H), 7.99 (d, J = 3.3 Hz, 1 H), 8.27 (d, J = 1.8 Hz, 1 H), 8.61 (d, J = 1.8 Hz, 1 H) MS m/z (M + H⁺) 505.2 1049 1-[2-(4-Fluorophenyl)ethyl]-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indazole ¹H NMR (400 MHz, acetone-d₆): δ 3.24 (t, J = 7.2 Hz, 2 H), 3.40 (br. s., 4 H), 4.09 (br. s., 2 H), 4.16-4.23 (m, 1 H), 4.31-4.65 (m, 4 H), 6 4.69 (t, J = 7.2 Hz, 2 H), 4.85 (br. s., 2 H), 6.96 (t, J = 8.8 Hz, 2 H), 7.19 (dd, J = 8.3, 5.6 Hz, 2 H), 7.49 (d, J = 8.8 Hz, 1 H), 7.62 (dd, J = 8.8, 1.3 Hz, 1 H), 7.93 (d, J = 3.0 Hz, 1 H), 8.00 (d, J = 3.0 Hz, 1 H), 8.09 (s, 1 H), 8.12 (s, 1 H) MS m/z (M + H⁺) 519.2 1050 2-[2-(4-Fluorophenyl)ethyl]-5-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2H- indazole ¹H NMR (400 MHz, acetone-d₆): δ 3.35 (t, J = 7.1 Hz, 2 H), 3.38-3.43 (m, 4 H), 4.09 (br. s., 2 H), 4.12-4.20 (m, 1 H), 4.31-4.69 (m, 4 6 H), 4.74 (t, J = 7.2 Hz, 2 H), 4.84 (br. s., 2 H), 7.01 (t, J = 8.7 Hz, 2 H), 7.21 (dd, J = 8.3, 5.6 Hz, 2 H), 7.55 (dd, J = 9.1, 1.5 Hz, 1 H), 7.66 (d, J = 9.1 Hz, 1 H), 7.93 (d, J = 3.0 Hz, 1 H), 8.00 (d, J = 3.3 Hz, 1 H), 8.03 (s, 1 H), 8.23 (s, 1 H) MS m/z (M + H⁺) 519.2 1051 1-(4-Fluorobenzyl)-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H- indazole ¹H NMR (400 MHz, acetone-d₆): δ 3.14-3.23 (m, 4 H), 3.91-4.00 (m, 1 H), 4.01-4.12 (m, 2 H), 4.26-4.56 (m, 3 H), 4.57-4.92 (m, 3 6 H), 5.74 (s, 2 H), 7.09 (t, J = 8.8 Hz, 2 H), 7.37-7.46 (m, 3 H), 7.84 (d, J = 8.3 Hz, 1 H), 7.89-7.95 (m, 2 H), 7.99 (d, J = 3.0 Hz, 1 H), 8.12 (s, 1 H) MS m/z (M + H⁺) 505.2 1052 2-(4-Fluorobenzyl)-6-({3-[4-(1,3-thiazol-2- ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-2H- indazole ¹H NMR (400 MHz, acetone-d₆): δ 3.21-3.30 (m, 4 H), 3.94-4.15 (m, 3 H), 4.28-4.52 (m, 2 H), 4.52-4.68 (m, 1 H), 4.68-4.93 (m, 3 6 H), 5.72 (s, 2 H), 7.15 (t, J = 8.8 Hz, 2 H), 7.34 (dd, J = 8.6, 1.3 Hz, 1 H), 7.45-7.52 (m, 2 H), 7.75 (d, J = 8.6 Hz, 1 H), 7.91 (s, 1 H), 7.92 (d, J = 3.3 Hz, 1 H), 7.99 (d, J = 3.3 Hz, 1 H), 8.42 (s, 1 H) MS m/z (M + H⁺) 505.2

Example 72a

D. Methyl 1-(4-cyanobenzyl)-1H-indazole-5-carboxylate, 72f

The title compound 72f was prepared using the procedure described in Example 72, substituting methyl 1H-indazole-5-carboxylate for 72a and substituting 4-(bromomethyl)benzonitrile for 72b. ¹H NMR (400 MHz, CDCl₃): δ 3.95 (s, 3H), 5.67 (s, 2H), 7.26 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.9 Hz, 1H), 7.61 (d, J=8.3 Hz, 2H), 8.06 (dd, J=8.9, 1.4 Hz, 1H), 8.18 (s, 1H), 8.55 (s, 1H). (M+H⁺) 292.2

E. 1-(4-cyanobenzyl)-1H-indazole-5-carboxylic acid, 72g, and 1-(4-carbamoylbenzyl)-1H-indazole-5-carboxylic acid, 72h

To a stirring solution of compound 72f (0.35 mmol, 102 mg) in 2 mL of THF and 0.5 mL of MeOH was added 3N aqueous NaOH (2.45 mmol, 0.82 mL). After stirring at room temperature overnight, the mixture was concentrated under vacuum. The yellow residue was dissolved in 15 mL of water and acidified to pH 1-2 with aqueous HCl. The resulting precipitate was vacuum-filtered through a paper disc and washed with water. The remaining material was pumped at high vacuum to give 87 mg of a 3:1 mixture (as shown by LC/MS) of compound 72g and compound 72h as an off-white solid. Compound 72g (less polar): MS m/z (M+H⁺) 278.1. Compound 72h (more polar): MS m/z (M+H⁺) 296.

F. 4-{[5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indazol-1-yl]methyl}benzonitrile, Cpd 1045, and 4-{[5-({3-[4-(1,3-Thiazol-2-ylcarbonyl)piperazin-1-yl]azetidin-1-yl}carbonyl)-1H-indazol-1-yl]methyl}benzamide, Cpd 1044

The title compounds Cpd 1045 and Cpd 1044 were prepared using the method described in Example 9, substituting the mixture of 72g and 72h prepared in Step E above for 9c and substituting HBTU for HATU in Step D. The products were separated by preparative reverse phase chromatography to give 64 mg of Cpd 1045 (less polar) and 6.4 mg of Cpd 1044 (more polar).

Cpd 1045:

¹H NMR (400 MHz, acetone-d₆): δ 3.24-3.49 (m, 4H), 4.00-4.11 (m, 2H), 4.11-4.20 (m, 1H), 4.26-4.96 (m, 6H), 5.85 (s, 2H), 7.45 (d, J=8.3 Hz, 2H), 7.66-7.72 (m, 2H), 7.74 (d, J=8.3 Hz, 2H), 7.92 (d, J=3.3 Hz, 1H), 7.99 (d, J=3.0 Hz, 1H), 8.16 (s, 1H), 8.20 (s, 1H)

Cpd 1044:

¹H NMR (400 MHz, acetone-d₆): δ 3.14 (br. s., 4H), 3.87-3.96 (m, 1H), 3.96-4.08 (m, 2H), 4.35 (br. s., 2H), 4.47-4.85 (m, 4H), 5.78 (s, 2H), 7.35 (d, J=8.3 Hz, 2H), 7.66 (s, J=8.8 Hz, 1H), 7.70 (d, J=8.6, 1.5 Hz, 1H), 7.88 (d, J=8.1 Hz, 2H), 7.91 (d, J=3.3 Hz, 1H), 7.98 (d, J=3.3 Hz, 1H), 8.16 (s, 1H), 8.18 (s, 1H)

BIOLOGICAL EXAMPLES In Vitro Methods Example 1 MGL Enzyme Activity Assay

All rate-based assays were performed in black 384-well polypropylene polymerase chain reaction (“PCR”) microplates (Abgene) in a total volume of 30 μL. Substrate 4-methylumbelliferyl butyrate (4MU-B; Sigma) and either purified mutant MGL (mut-MGLL 11-313 L179S L186S) or purified wild type MGL (wt-MGLL 6H-11-313) were diluted separately into 20 mM 1,4-piperazinediethanesulfonic acid (“PIPES”) buffer (pH=7.0), containing 150 mM NaCl and 0.001% Tween 20. Compounds of Formula (I) were pre-dispensed (50 mL) into the assay plate using a Cartesian Hummingbird prior to adding 4MU-B (25 μL, of 1.2× solution to a final concentration of 10 μM) followed by enzyme (5 μL, of a 6× solution to a final concentration of 5 nM) to initiate the reaction. Final compound concentrations ranged from 17 to 0.0003 μM. The fluorescence change due to 4MU-B cleavage was monitored with excitation and emission wavelengths of 335 and 440 nm, respectively, and a bandwidth of 10 nm (Safire², Tecan) at 37° C. for 5 min

The IC₅₀ values for compounds of Formula (I) were determined using Excel from a fit of the equation to the concentration-response plot of the fractional activity as a function of inhibitor concentration.

BIOLOGICAL DATA TABLE 1 Chemistry MGL mutant MGL wild type Cpd Example inh IC₅₀ (μM) inh IC₅₀ (μM) 1  1 0.0283 2  1 0.0081 3  1 5.20 4  1 0.731 5  1 0.0657 0.523 6  1 0.0080 7  1 0.0346 0.131 8  1 0.101 9  1 0.0087 0.0174 10  1 0.329 11  1 2.86 12  1 0.0470 13  1 0.0200 0.0192 14  1 1.22 15  1 2.18 16  1 0.828 17  1 14.3 18  1 0.124 19  1 0.979 20  1 1.89 21  1 2.35 22  1 4.81 23  1 2.78 24  1 2.45 25  1 2.29 26  1 15.4 567  1 0.018 0.015 579  1 0.065 581  1 0.080 587  1 0.014 0.119 595  1 0.098 0.500 598  1 0.979 1061  1 0.006 1071  1 0.008 1139  1 0.027 1147  1 0.032 1163  1 0.009 0.048 1174  1 <0.005 0.066 1201  1 0.007 0.151 1248  1 0.559 1356  1 <0.005 <0.005 1357  1 <0.005 <0.005 1358  1 <0.005 <0.005 1359  1 <0.005 <0.005 1360  1 <0.005 <0.005 1361  1 <0.005 1362  1 <0.005 1363  1 <0.005 1364  1 <0.005 1366  1 <0.005 1382  1 0.069 1408  1 <0.005 586  1b 0.112 596  1b 0.543 603  1b 1.722 630  1b 0.714 1062  1b 0.007 1072  1b 0.008 1073  1b 0.034 1089  1b 0.010 1097  1b 0.012 1105  1b 0.013 1107  1b 0.014 1120  1b 0.018 1121  1b 0.018 1126  1b 0.019 1127  1b 0.020 1128  1b 0.021 1134  1b 0.025 1135  1b 0.025 1176  1b 0.070 1181  1b 0.077 1189  1b 0.097 1192  1b 0.109 1197  1b 0.133 1216  1b 0.216 1219  1b 0.235 1230  1b 0.307 1247  1b 0.539 1263  1b 0.968 1312  1b <0.00500035 1314  1b <0.00500035 1337  1b <0.00500035 1338  1b <0.00500035 1339  1b <0.00500035 1410  1b 0.089 656  1c 0.008 1079  1c 0.009 1184  1c 0.086 1199  1c 0.146 1141  1d 0.010 0.028 1151  1d 0.037 1158  1d 0.042 592  1e 0.078 0.253 1125  1e <0.00500035 0.019 1187  1e <0.00500035 0.092 629  1f 0.053 1180  1f 0.075 1313  1f <0.00500035 1409  1g 27  2 14.5 487  1a <0.005 0.0104 28  2 1.63 29  2 0.363 30  2 0.670 31  2 5.07 32  2 0.761 33  2 0.633 34  2 1.38 35  2 0.459 36  2 0.115 37  2 0.117 5.99 38  2 0.666 39  2 0.0317 0.0147 40  2 0.0491 41  2 0.0322 42  2 0.354 43  2 0.0310 1.26 44  2 0.0700 45  2 3.42 46  2 3.43 47  2 0.129 0.129 48  2 0.551 49  2 5.78 50  2 8.71 51  2 0.227 52  2 1.94 53  2 0.988 54  2 0.223 55  2 0.307 56  2 13.8 57  2 5.24 58  2 2.63 59  2 3.38 60  2 2.66 461  2 5.28 462  2 5.05 463  2 9.63 464  2 5.82 465  2 8.27 466  2 10.9 467  2 9.82 468  2 2.70 469  2 2.25 470  2 7.06 471  2 3.38 472  2 9.73 531  2 0.766 539  2 11.476 541  2 13.059 559  2 1.287 562  2 13.474 565  2 11.392 622  2 1.360 627  2 13.225 628  2 13.502 954  2 2.743 1266  2 1.083 1284  2 2.292 1404  2 13.286 1482  2 >16.9981 1483  2 >16.6686 1485  2 >16.6686 1464  2 >16.6686 61  3 0.0385 676  3 <0.005 0.021 703  3 0.014 0.088 716  3 0.023 0.140 722  3 0.051 0.180 741  3 0.038 0.298 753  3 0.075 0.434 921  3 6.331 1067  3 <0.005 0.007 1166  3 0.052 1235  3 0.030 0.360 1236  3 0.042 0.390 1242  3 0.146 0.461 1243  3 0.463 1246  3 0.207 0.506 1276  3 0.650 1.764 1283  3 0.063 2.171 1292  3 0.244 3.070 1383  3 0.081 1400  3 5.929 1401  3 8.843 1402  3 9.972 62  4 2.95 63  4 4.84 64  4 2.29 65  4 0.893 66  4 1.40 67  4 0.134 68  4 12.7 69  4 4.31 70  4 4.83 71  4 7.58 72  4 0.0270 0.326 73  4 1.54 74  4 3.34 75  4 0.0939 76  4 2.43 77  4 0.0478 78  4 0.607 79  4 0.125 80  4 4.85 81  4 0.227 82  4 0.466 83  4 0.0989 474  4 4.68 473  4 9.79 84  4 4.67 85  4 4.17 86  4 3.92 87  4 4.81 88  4 1.95 89  4 1.76 90  4 14.7 91  4 1.87 92  4 13.6 93  4 3.93 94  4 1.88 95  4 0.669 96  4 14.0 97  4 0.920 98  4 4.58 99  4 6.36 100  4 3.50 101  4 0.299 102  4 3.04 103  4 8.93 104  4 3.90 105  4 2.97 106  4 0.539 107  4 1.12 108  4 8.63 109  4 0.0385 110  4 1.22 111  4 14.0 496  4 1.30 558  4 0.410 618  4 0.140 619  4 0.142 620  4 0.153 621  4 0.271 623  4 2.423 624  4 4.687 625  4 9.761 626  4 12.74 133  5 <0.005 0.0673 134  5 0.0114 135  5 <0.005 136  5 <0.005 137  5 0.0073 138  5 <0.005 139  5 0.968 140  5 0.653 141  5 0.412 142  5 1.55 143  5 7.14 144  5 4.68 145  5 2.69 146  5 0.518 147  5 <0.005 148  5 <0.005 <0.005 149  5 0.249 0.0769 150  5 0.0058 <0.005 151  5 0.114 152  5 3.51 153  5 0.355 154  5 0.127 155  5 3.75 156  5 1.54 157  5 0.853 158  5 0.0339 0.657 159  5 0.682 160  5 2.54 161  5 0.0050 0.0117 162  5 <0.005 163  5 0.0239 164  5 0.0100 165  5 0.451 166  5 <0.005 <0.005 167  5 0.0500 0.0152 168  5 0.0059 <0.005 169  5 5.55 170  5 0.0679 171  5 0.380 172  5 0.0088 0.0073 475  5 0.234 476  5 0.0443 0.338 477  5 1.38 478  5 3.12 479  5 2.82 298  5 1.16 112  5 1.08 113  5 0.587 114  5 0.840 115  5 0.0180 0.0117 116  5 1.49 117  5 0.396 4.23 489  5 <0.005 0.0090 490  5 <0.005 0.0223 485  5 <0.005 0.102 502  5 6.091 503  5 0.152 517  5 0.073 1.340 523  5 3.135 524  5 4.368 526  5 8.102 610  5 10.347 611  5 13.253 636  5 0.021 637  5 0.041 638  5 0.189 639  5 0.419 640  5 15.944 641  5 <0.005 643  5 0.411 644  5 3.086 646  5 7.158 648  5 0.018 655  5 0.008 658  5 0.009 667  5 0.014 669  5 0.015 672  5 0.017 675  5 0.019 678  5 0.022 682  5 0.030 687  5 0.044 688  5 0.044 693  5 0.047 694  5 0.047 696  5 0.059 698  5 0.065 702  5 0.303 710  5 0.123 719  5 0.154 721  5 0.173 726  5 0.218 727  5 0.219 728  5 0.231 730  5 0.238 731  5 0.238 732  5 0.239 733  5 0.240 735  5 0.268 739  5 0.290 740  5 0.294 743  5 0.324 744  5 0.335 746  5 0.373 747  5 0.377 748  5 0.384 750  5 0.395 751  5 0.402 754  5 0.447 755  5 0.468 756  5 0.519 758  5 0.535 760  5 0.581 762  5 0.632 763  5 0.635 764  5 0.636 766  5 0.680 768  5 0.697 770  5 0.740 772  5 0.799 774  5 0.848 776  5 0.902 779  5 0.944 781  5 1.042 782  5 1.066 783  5 1.086 785  5 1.190 786  5 1.203 787  5 1.209 788  5 1.227 791  5 1.448 792  5 1.458 793  5 1.460 794  5 1.469 795  5 1.502 796  5 1.529 797  5 1.596 799  5 1.667 800  5 1.696 804  5 0.058 1.993 808  5 2.076 809  5 2.104 814  5 2.434 815  5 2.492 816  5 2.636 818  5 2.702 821  5 2.847 823  5 2.970 824  5 3.120 825  5 3.148 826  5 3.287 827  5 3.308 828  5 3.733 830  5 3.942 831  5 4.097 835  5 4.705 836  5 4.756 838  5 5.113 839  5 5.135 840  5 5.155 842  5 5.526 843  5 5.531 844  5 6.104 845  5 6.421 846  5 6.448 848  5 6.902 849  5 7.011 850  5 7.278 852  5 8.078 853  5 8.344 854  5 >16.6686 8.414 855  5 8.435 857  5 8.724 859  5 8.815 860  5 8.819 862  5 9.510 863  5 10.158 864  5 10.221 865  5 10.287 868  5 12.112 871  5 13.323 873  5 14.703 874  5 15.209 886  5 <0.005 887  5 <0.005 888  5 <0.005 889  5 <0.005 890  5 <0.005 891  5 <0.005 892  5 <0.005 893  5 <0.005 894  5 <0.005 905  5 0.015 910  5 0.194 912  5 0.472 915  5 0.944 923  5 8.756 925  5 9.968 926  5 10.457 946  5 1.001 947  5 1.065 952  5 0.012 953  5 >16.6686 965  5 0.037 966  5 0.222 993  5 1.514 1000  5 0.111 1001  5 1.403 1002  5 5.292 1003  5 1.613 1004  5 0.167 1017  5 0.035 1041  5 0.019 1042  5 5.274 1053  5 0.018 1082  5 0.009 1083  5 0.009 1103  5 0.013 1119  5 0.017 1122  5 0.018 1123  5 0.019 1146  5 0.032 1150  5 <0.005 0.036 1156  5 0.041 1164  5 0.048 1179  5 0.073 1194  5 0.118 1202  5 0.152 1203  5 0.153 1214  5 0.209 1218  5 0.222 1223  5 0.267 1225  5 0.273 1245  5 0.500 1249  5 0.605 1271  5 1.568 1272  5 1.608 1287  5 2.450 1293  5 3.172 1297  5 3.311 1298  5 3.850 1299  5 3.856 1300  5 4.135 1301  5 4.608 1305  5 6.676 1307  5 8.776 1326  5 <0.005 1327  5 <0.005 1328  5 <0.005 1329  5 <0.005 1330  5 <0.005 1331  5 <0.005 1332  5 <0.005 1333  5 <0.005 1334  5 <0.005 1378  5 0.009 1379  5 0.022 1381  5 0.065 1384  5 0.092 1385  5 0.152 1386  5 0.180 1392  5 0.693 1395  5 0.866 1396  5 1.159 1397  5 1.165 1403  5 12.331 1407  5 <0.005 1412  5 0.087 1442  5 >16.6686 1444  5 >16.6686 1445  5 >16.6686 1491  5 >16.6686 1460  5 >16.6686 1434  5 >16.6686 1477  5 >16.6686 1432  5 >16.6686 1489  5 >16.6686 >16.6686 1490  5 >16.6686 1481  5 >16.6686 1436  5 >16.6686 >16.6686 1473  5 >16.6686 1475  5 >16.6686 1446  5 >16.6686 1447  5 >16.6686 1448  5 >16.6686 1449  5 >16.6686 1450  5 >16.6686 1451  5 >16.6686 1452  5 >16.6686 1453  5 >16.6686 173  6 0.532 174  6 0.0062 175  6 <0.005 <0.005 176  6 <0.005 177  6 0.0088 178  6 <0.005 179  6 0.0069 180  6 <0.005 181  6 <0.005 182  6 <0.005 183  6 <0.005 184  6 0.0385 185  6 2.63 186  6 0.0068 0.0184 187  6 0.546 188  6 0.0409 189  6 0.651 190  6 2.51 191  6 1.46 192  6 2.36 193  6 0.460 194  6 0.553 195  6 0.0824 196  6 0.0159 0.216 197  6 0.931 198  6 0.211 199  6 5.46 200  6 0.168 201  6 1.57 202  6 0.477 203  6 1.05 204  6 0.371 205  6 0.0189 206  6 1.36 207  6 0.0098 208  6 0.0190 0.0920 209  6 0.0170 210  6 0.0101 211  6 0.0143 212  6 <0.005 <0.005 213  6 <0.005 214  6 <0.005 215  6 0.0540 216  6 0.0113 217  6 0.561 218  6 0.0200 219  6 0.0145 0.0320 220  6 <0.005 221  6 <0.005 222  6 0.242 223  6 0.0164 224  6 <0.005 225  6 0.0523 0.0547 226  6 0.0696 227  6 <0.005 0.0070 228  6 0.0204 <0.005 229  6 <0.005 <0.005 230  6 0.0116 231  6 0.516 232  6 <0.005 0.0829 233  6 1.78 234  6 0.157 235  6 1.70 236  6 0.499 237  6 <0.005 <0.005 238  6 0.0516 239  6 <0.005 0.0100 240  6 <0.005 0.0508 241  6 0.0070 242  6 <0.005 243  6 0.0057 244  6 <0.005 245  6 <0.005 0.0164 246  6 0.0200 247  6 <0.005 248  6 <0.005 0.0070 249  6 0.0120 250  6 <0.005 <0.005 251  6 <0.005 0.0170 252  6 0.0125 0.0808 253  6 <0.005 0.0494 254  6 <0.005 <0.005 255  6 0.0102 256  6 0.0110 0.0134 257  6 <0.005 <0.005 258  6 <0.005 259  6 0.0060 260  6 0.0089 261  6 <0.005 0.0084 262  6 <0.005 <0.005 263  6 <0.005 0.0285 264  6 0.0050 265  6 <0.005 0.0190 266  6 <0.005 0.0498 267  6 <0.005 268  6 0.0544 488  6 0.0173 0.382 1070  6 <0.005 0.008 1102  6 <0.005 0.013 269  7 0.215 270  7 0.289 271  7 0.210 272  7 2.71 273  7 0.0872 274  7 0.0705 275  7 1.07 276  7 0.341 277  7 4.70 278  7 4.18 279  7 0.640 280  7 0.141 281  7 0.0930 282  7 <0.005 283  7 0.0222 284  7 4.88 285  7 13.2 286  7 0.150 287  7 6.81 288  7 3.54 289  7 6.56 290  7 0.0600 291  7 0.0071 292  7 2.59 293  7 0.380 294  7 0.638 295  7 2.13 296  7 1.04 297  7 0.358 299  8 0.683 300  8 6.99 301  8 0.326 302  8 0.143 303  8 0.314 0.173 304  8 0.358 305  8 0.132 306  8 0.666 307  8 0.408 308  8 6.07 309  8 1.17 310  8 0.0842 311  8 0.0640 312  8 0.0065 480  8 3.38 1057  8 0.006 1078  8 0.009 1085  8 0.009 1087  8 0.009 1094  8 0.011 1112  8 0.016 1118  8 0.016 1140  8 0.027 1143  8 0.030 1145  8 0.031 1169  8 0.055 1217  8 0.220 1222  8 0.266 1232  8 0.326 1256  8 0.808 1258  8 0.829 1262  8 0.950 1269  8 1.264 1308  8 9.277 1310  8 11.649 1324  8 <0.005 1325  8 <0.005 1335  8 <0.005 1336  8 <0.005 1398  8 1.222 1423  8 0.278 1424  8 0.075 1425  8 0.009 1426  8 <0.005 1427  8 0.006 1428  8 0.014 1429  8 0.036 186-A  8 0.010 567-A  8 0.028 1478  8 >16.6686 1465  8 >16.6686 313  9 <0.005 314  9 0.0100 <0.005 315  9 5.00 316  9 <0.005 <0.005 317  9 0.0050 <0.005 318  9 <0.005 0.0139 319  9 0.0088 320  9 8.53 321  9 0.0378 322  9 13.7 606  9 2.038 647  9 12.723 654  9 0.007 681  9 0.027 713  9 0.135 718  9 0.148 723  9 0.181 745  9 0.342 767  9 0.691 775  9 0.862 806  9 2.052 812  9 2.192 817  9 2.700 820  9 2.815 822  9 2.856 829  9 3.905 832  9 4.239 856  9 8.486 918  9 2.891 1054  9 0.005 1055  9 0.005 1056  9 0.006 1068  9 0.007 1077  9 0.008 1088  9 0.010 1090  9 0.010 1106  9 0.014 1110  9 0.015 1116  9 0.016 1129  9 0.021 1131  9 0.022 1152  9 0.038 1153  9 0.039 1178  9 0.071 1198  9 0.143 1224  9 0.270 1226  9 0.282 1233  9 0.343 1261  9 0.932 1275  9 1.722 1277  9 1.834 1279  9 1.902 1286  9 2.417 1295  9 3.278 1302  9 4.948 1306  9 8.151 1320  9 <0.005 1367  9 <0.005 1368  9 <0.005 1369  9 <0.005 1370  9 <0.005 1371  9 <0.005 1372  9 <0.005 1373  9 <0.005 1413  9 0.015 1492  9 >16.6686 1499  9 >16.6686 118  9b 0.664 119  9b 3.17 120  9b 0.0783 121  9b 1.91 122  9b 5.97 123  9b 0.591 124  9b 0.118 0.321 125  9b 0.322 126  9b 0.0510 0.0200 127  9b 0.499 128  9b 0.0045 129  9b 0.281 130  9b 0.823 131  9b 0.0767 132  9b 0.880 568  9b 0.072 569  9b 0.021 571  9b 0.028 573  9b 0.046 577  9b 0.052 578  9b 0.063 580  9b 0.069 583  9b 0.104 584  9b 0.105 590  9b 0.186 599  9b 1.031 617  9b 0.102 566  9c 0.014 1375  9c <0.005 1421  9c <0.005 582  9d 0.097 588  9d 0.142 594  9d 0.449 1109  9d 0.015 1113  9d 0.016 1133  9d 0.024 1159  9d 0.045 1171  9d 0.063 1177  9d 0.063 1182  9d 0.079 633  9e 0.062 1115  9e 0.016 575  9f 0.051 576  9f 0.051 1080  9f 0.009 1374  9f <0.005 1376  9f <0.005 1419  9f <0.005 1420  9f 0.005 1422  9f 0.014 1165  9g 0.051 1210  9g 0.195 819  9h 2.790 601  9i 0.490 1.552 602  9i 0.302 1.717 607  9i 0.894 2.905 608  9i 0.766 4.166 609  9i 0.735 4.332 980  9i 2.442 6.792 989  9i 1.566 990  9i 3.870 991  9i 0.564 1252  9i 0.136 0.706 1255  9i <0.005 0.769 1290  9i 0.187 2.700 1387  9i 0.300 1388  9i 0.351 1389  9i 0.379 1390  9i 0.461 1391  9i 0.505 1393  9i 0.726 1394  9i 0.756 1399  9i 2.373 1154  9j <0.005 0.040 1173  9j 0.065 1190  9j 0.099 1191  9j 0.105 1193  9j 0.116 1220  9j 0.255 1237  9j 0.393 1238  9j <0.005 0.437 1251  9j 0.684 1254  9j 0.023 0.765 1257  9j 0.827 1282  9j 0.019 2.072 323 10 0.0110 324 10 <0.005 <0.005 325 10 0.0150 0.0695 686 10 0.039 749 10 0.387 778 10 0.933 801 10 1.712 833 10 4.562 650 10a 0.006 666 10a 0.013 670 10a 0.015 900 10a <0.005 659 10b 0.009 697 10b 0.062 901 10b <0.005 902 10b <0.005 326 11 <0.005 <0.005 327 11 0.0089 328 11 0.0540 329 11 0.0358 1.22 330 11 0.0440 0.308 331 11 <0.005 0.0457 332 11 0.0117 333 11 <0.005 0.0162 334 11 0.0143 0.363 335 11 0.0060 0.0121 336 11 <0.005 <0.005 337 11 <0.005 0.0130 504 11 <0.005 0.010 516 11 0.465 543 11 <0.005 684 11 0.031 742 11 0.306 810 11 2.143 897 11 <0.005 <0.005 898 11 <0.005 <0.005 908 11 0.031 929 11 <0.005 930 11 <0.005 338 12 <0.005 <0.005 339 12 0.113 340 12 0.843 341 12 3.63 342 12 0.0440 343 13 0.0059 344 13 0.0270 345 13 <0.005 <0.005 511 13 0.240 515 13 0.455 591 13 0.212 346 14 2.83 347 14 0.0877 600 14 1.154 605 14 1.861 917 14 2.107 919 14 4.004 920 14 4.427 924 14 9.685 1059 14 0.006 1060 14 0.006 1065 14 0.007 1066 14 0.007 1096 14 0.011 1101 14 0.012 1157 14 0.041 1160 14 0.045 1183 14 0.085 1321 14 <0.005 1342 14 <0.005 1343 14 <0.005 1351 14 <0.005 1352 14 <0.005 1353 14 <0.005 1354 14 <0.005 1075 14a 0.008 1149 14a 0.035 1175 14a 0.066 1205 14a 0.168 1196 14b 0.123 1204 14b 0.166 1211 14b 0.200 1241 14b 0.460 1244 14b 0.463 1209 14c 0.193 1213 14c 0.206 1294 14d 3.229 1303 14d 5.112 1443 14d >16.6686 1476 14d >16.6686 348 15 1.16 349 16 1.03 350 17 0.0991 351 17 1.97 352 17 1.67 353 17 3.97 354 17 1.56 546 17 1437 17 >16.6686 1486 17 >16.6686 >16.6686 538 17a 8.813 861 17a 9.221 903 17a 0.009 690 17b 0.046 916 17b 1.683 355 18 2.05 356 19 1.62 357 20 0.0385 3.75 358 21 0.0670 359 21 0.0094 360 21 0.0060 361 21 0.0355 362 21 0.542 363 21 3.12 364 21 0.0085 0.210 365 21 0.0332 665 21 0.013 679 21 0.010 0.024 685 21 0.029 0.033 729 21 0.236 736 21 <0.005 0.273 907 21 0.029 366 22 <0.005 367 22 0.0080 368 22 0.0050 369 22 0.165 370 23 <0.005 371 23 <0.005 879 23 0.006 <0.005 880 23 0.025 <0.005 680 23a 0.025 1458 23a >16.6686 372 24 <0.005 373 24 <0.005 374 24 <0.005 375 24 0.0414 661 24 0.010 668 24 0.015 805 24 1.995 883 24 <0.005 376 25 1.08 377 25 3.35 378 25 5.06 379 26 0.0367 380 26 0.0542 381 26 0.0099 <0.005 382 26 0.913 383 26 0.476 384 26 0.349 385 26 0.110 386 26 1.25 387 26 0.348 388 26 0.429 389 26 9.27 390 26 2.43 391 26 0.227 392 26 0.558 393 26 0.141 394 26 0.434 395 26 0.437 396 26 0.790 397 27 0.0180 398 27 0.0254 399 27 0.0312 400 27 <0.005 401 27 <0.005 402 27 0.0476 403 27 0.0958 404 27 0.0418 405 27 0.0067 406 27 0.0831 407 27 <0.005 0.0506 408 27 0.239 409 27 1.39 481 27 0.244 482 27 0.236 483 27 0.338 484 27 0.696 552 27 0.147 560 27 1.978 957 27 <0.005 <0.005 960 27 0.007 962 27 <0.00500035 963 27 0.190 967 27 0.020 0.009 970 27 0.805 972 27 0.013 0.023 983 27 0.006 987 27 0.071 554 27a 0.179 978 27a <0.00500035 0.007 981 27a 0.186 958 27b 0.313 961 27b 1.122 968 27b 0.019 979 27b 0.648 984 27b 2.497 410 28 0.0253 411 28 0.0478 412 28 0.0249 413 28 0.0406 414 28 0.0144 415 28 0.0110 416 28 0.0129 417 28 0.197 418 28 0.315 550 28 0.114 555 28 0.196 973 28 <0.005 975 28 1.174 0.162 974 28a 0.177 419 29 0.0070 0.170 420 29 0.0112 421 29 0.0060 422 29 0.0568 423 29 0.0050 424 29 <0.005 <0.005 425 29 0.160 426 29 0.278 662 29 0.021 0.011 931 29a 427 30 0.0334 428 30 <0.005 429 30 <0.005 430 30 0.0180 0.0236 431 30 <0.005 432 30 <0.005 <0.005 677 30a 0.021 790 30a 1.417 433 31 0.0249 508 31 0.006 0.107 651 31 <0.005 0.007 738 31 0.065 0.289 876 31 <0.005 <0.005 1507 31 >16.6686 564 31a 4.633 5.400 971 31a 1.536 976 31a 0.566 0.574 977 31a 5.563 807 31b 2.075 914 31c 0.760 1493 31c >16.6686 1498 31c >16.6686 434 32 0.0647 435 32 0.0267 436 32 0.331 437 32 1.52 438 32 0.977 439 33 0.672 440 33 4.07 441 33 10.3 442 33 3.78 443 33 3.35 444 33 3.22 445 33 2.28 446 33 2.36 447 33 0.667 448 33 1.90 449 33 8.12 450 34 0.0088 451 34 0.652 452 34 0.288 453 35 <0.005 454 35 0.0060 455 35 <0.005 548 35 0.027 959 35 0.005 <0.005 549 35a 0.104 551 35a 0.125 956 35a 0.048 969 35a 0.077 955 35b 0.713 964 35b 1.701 456 36 1.98 457 37 0.876 458 37 3.72 459 37 0.950 460 37 0.548 497 38 2.36 498 38 0.679 499 38 0.418 500 38 1.18 501 38 >16.7 495 39 >16.7 491 39 0.254 492 39 0.0788 493 39 0.169 494 39 0.0771 642 40 0.069 645 40 5.207 1488 41 >16.6686 1457 41 >16.6686 996 42 <0.005 997 42 <0.005 1006 42 0.374 1016 42 0.085 547 42 <0.005 563 42 2.493 985 42 0.008 995 42 <0.005 998 42 <0.005 999 42 0.008 1007 42 0.027 1008 42 <0.005 1009 42 0.065 1013 42 0.161 1014 42 0.257 1015 42 0.777 771 42 0.007 948 43 0.011 949 43 0.163 950 43 1.501 1025 43 0.019 507 44 0.013 0.052 518 44 1.605 520 44 2.027 522 44 2.680 525 44 6.995 527 44 3.512 8.566 532 44 1.419 533 44 1.804 537 44 7.588 652 44 0.007 663 44 <0.005 0.011 715 44 0.135 717 44 0.147 734 44 0.163 0.256 752 44 0.421 765 44 0.236 0.667 875 44 <0.005 <0.005 877 44 0.012 <0.005 904 44 0.011 909 44 0.074 913 44 0.516 1484 44 >16.6686 802 44a 1.721 837 44a 5.036 869 44a 12.871 872 44a 13.954 720 44b 0.173 757 44b 0.530 769 44b 0.725 784 44b 1.125 922 44b 6.494 514 45 0.454 519 45 1.620 521 45 2.190 660 45 0.010 683 45 0.031 708 45 0.106 878 45 <0.005 1494 45a >16.6686 689 45b 0.045 803 45b 1.868 811 45b 2.151 1010 46 <0.005 1011 46 <0.005 1018 46 0.101 1019 46 0.006 1021 46 0.015 1023 46 0.041 1024 46 0.069 1267 46 1.125 1304 46 6.035 1309 46 9.363 1012 46a 0.013 1020 46a 0.063 1022 46a 0.067 1311 46a 14.615 529 47 0.147 530 47 0.165 542 47 <0.005 553 47 0.176 556 47 0.293 557 47 0.340 561 47 2.745 1005 47 0.237 709 48 0.118 671 49 0.016 1365 50 <0.005 1417 51 <0.005 1418 51 0.016 1063 52 0.007 1092 52 0.011 1315 52 <0.005 1316 53 <0.005 1317 53 <0.005 1319 53 <0.005 1142 53a 0.029 1318 53a <0.005 597 54 0.600 604 54 1.841 1086 54 0.009 1130 54 0.022 1137 54 0.026 1170 54 0.059 1195 54 0.120 884 55 <0.005 885 55 <0.005 1081 55 0.009 1099 55 0.012 881 55a <0.005 882 55a <0.005 994 55a 0.013 724 55b 0.206 773 55b 0.845 1026 56 0.016 1027 56 0.014 1028 56 0.016 1033 56 <0.005 1034 56 <0.005 992 57 7.761 1430 57 9.892 1431 57 0.589 911 58 0.272 988 58 0.036 612 59 0.016 613 59 0.019 614 59 0.025 615 59 0.026 616 59 0.076 706 59 0.103 1074 59 0.014 0.008 1091 59 0.011 0.011 1093 59 <0.005 0.011 1104 59 <0.005 0.013 1108 59 0.019 0.014 1114 59 0.016 1117 59 <0.005 0.016 1124 59 <0.005 0.019 1138 59 0.026 1144 59 0.006 0.031 1168 59 <0.005 0.053 1172 59 0.010 0.063 1185 59 0.007 0.088 1188 59 0.027 0.094 1200 59 0.020 0.151 1208 59 <0.005 0.190 1221 59 0.008 0.258 1228 59 0.249 0.295 1234 59 0.024 0.356 1239 59 0.338 0.449 1240 59 0.139 0.459 1250 59 0.174 0.638 1253 59 0.031 0.725 1259 59 0.062 0.847 1265 59 0.072 1.050 1268 59 1.220 1273 59 0.234 1.609 1278 59 1.392 1.863 1280 59 0.239 1.978 1285 59 1.041 2.317 1288 59 1.123 2.511 1322 59 <0.005 <0.005 1323 59 0.012 <0.005 1377 59 0.004 1405 59 <0.005 1406 59 <0.005 1136 59a 0.025 1161 59a 0.046 1162 59a 0.047 1212 59a 0.204 1260 59a 0.862 759 60 0.579 761 60 0.583 780 60 0.978 834 60 4.595 841 60 5.257 851 60 7.870 1064 60 0.007 1167 60 0.053 1186 60 0.088 1207 60 0.179 1231 60 0.316 1270 60 1.429 1274 60 1.660 1281 60 2.023 635 60a 0.838 777 60a 0.913 789 60a 1.366 798 60a 1.630 858 60a 8.772 866 60a 10.325 1206 60a 0.171 1215 60a 0.216 1227 60a 0.287 1229 60a 0.306 1264 60a 0.986 1289 60a 2.603 1291 60a 2.785 1296 60a 3.299 1506 60a >16.6686 932 60b 0.104 933 60b 0.191 934 60b 0.174 935 60b 0.100 936 60b 0.013 937 60b 0.250 938 60b 0.698 939 60b 2.357 940 60b 2.237 941 60b 1.372 942 60b 0.216 943 60b 10.387 944 60b 7.322 945 60b 1.476 509 61 0.136 653 61 0.007 895 61 <0.005 585 62 0.107 593 62 0.311 701 62 0.077 1084 62 0.009 1100 62 0.012 1132 62 <0.005 0.023 1148 62 0.033 1155 62 0.041 1347 62 <0.005 572 62a 0.031 634 62a 0.057 1340 62a <0.005 1341 62a <0.005 1344 62a <0.005 1345 62a <0.005 982 63 0.010 <0.005 986 64 0.005 510 65 0.181 513 65 0.371 528 65 0.125 570 65 0.022 691 65 0.046 695 65 0.057 707 65 0.105 712 65 0.127 714 65 0.135 737 65 0.285 1058 65 0.006 1095 65 0.011 1098 65 0.012 1346 65 <0.005 951 66 0.540 506 67 0.048 673 67 0.017 896 67 <0.005 512 67a 0.260 664 67a 0.011 699 67a 0.069 505 67b <0.005 0.039 657 67b 0.009 674 67b <0.005 0.019 692 67b 0.047 899 67b <0.005 <0.005 649 68 0.006 700 68 0.072 704 68a 0.096 705 68a 0.099 574 69 0.049 589 69 0.146 631 70 0.040 632 70 0.281 1069 70 0.007 1348 70 <0.005 1349 70 <0.005 1111 70a 0.016 1350 70a <0.005 1076 70b 0.008 1355 70b <0.005 1414 70c 0.011 1415 70c 0.115 1416 70c 0.039 711 71 0.127 813 71 2.422 1031 71 0.111 1032 71 3.020 1035 71 4.622 1046 71 0.288 1047 71 4.628 1048 71 0.695 1029 72 <0.005 1030 72 0.013 1036 72 <0.005 1037 72 0.005 1038 72 <0.005 1039 72 0.005 1040 72 0.025 1043 72 0.016 1049 72 0.010 1050 72 0.024 1051 72 0.128 1052 72 0.028 1411 72 0.012 1044 72a 0.718 1045 72a 0.021 1508 0.046

Example 2 2-AG Accumulation Assay

To measure the accumulation of 2-AG due to inhibition of MGL, one g rat brain was homogenized using a Polytron homogenizer (Brinkmann, PT300) in 10 mL of 20 mM HEPES buffer (pH=7.4), containing 125 mM NaCl, 1 mM EDTA, 5 mM KCl and 20 mM glucose. Compounds of Formula (I) (10 μM) were pre-incubated with rat brain homogenate (50 mg). After a 15-min incubation time at 37° C., CaCl₂ (final concentration=10 mM) was added and then incubated for 15 min at 37° C. in a total volume of 5 mL. The reactions were stopped with 6 mL organic solvent extraction solution of 2:1 chloroform/methanol. Accumulated 2-AG in the organic phase was measured by a HPLC/MS method, according to the following equation: percent vehicle=(2-AG accumulation in the presence of compound/2-AG accumulation in vehicle)×100.

BIOLOGICAL DATA TABLE 2 Rat Brain 2AG % VehCntrl Chemistry (%) (%) Cpd Example @0.01 μM @0.1 μM (%) @1 μM (%) @10 μM 2  1 911 5  1 122 123 156 279 6  1 75 238 554 623 7  1 216 238 568 9  1 99 184 529 1026 12  1 448 13  1 730 567  1 455 579  1 265 581  1 140 587  1 148 595  1 128 1061  1 618 1071  1 552 1139  1 654 1147  1 892 1163  1 244 1174  1 1021 1201  1 475 1356  1 1420 1357  1 2570 1358  1 1183 1359  1 1016 1360  1 576 1361  1 994 1362  1 635 1363  1 628 1364  1 944 1366  1 586 1382  1 293 1408  1 1475 487  1a 463 2081 2182 1062  1b 451 1072  1b 839 1073  1b 749 1089  1b 545 1097  1b 422 1105  1b 734 1107  1b 838 1120  1b 867 1126  1b 850 1134  1b 774 1135  1b 884 1176  1b 378 1181  1b 288 1312  1b 963 1337  1b 979 1338  1b 877 1339  1b 574 1184  1c 401 1141  1d 148 442 996 1151  1d 482 1158  1d 1623 1125  1e 1228 1187  1e 319 1313  1f 851 39  2 173 168 277 40  2 490 41  2 544 43  2 215 44  2 238 61  3 604 676  3 437 703  3 346 716  3 326 722  3 240 741  3 182 753  3 173 1067  3 408 1166  3 176 1235  3 100 1236  3 167 1283  3 62 72  4 334 75  4 193 77  4 231 83  4 105 133  5 623 134  5 582 135  5 592 136  5 612 137  5 441 138  5 661 147  5 676 148  5 744 150  5 1104 158  5 126 213 161  5 335 1280 162  5 1099 163  5 923 164  5 969 166  5 509 167  5 481 168  5 813 170  5 205 172  5 217 476  5 272 115  5 579 485  5 208 396 818 489  5 119 235 790 950 490  5 208 343 756 886 636  5 296 637  5 272 641  5 397 648  5 126 655  5 359 658  5 351 667  5 856 669  5 583 672  5 268 675  5 330 678  5 234 682  5 390 687  5 698 688  5 373 693  5 299 696  5 444 702  5 848 886  5 823 887  5 270 888  5 940 889  5 683 890  5 823 891  5 422 892  5 948 893  5 626 894  5 534 905  5 119 965  5 591 1017  5 307 1082  5 742 1083  5 299 1103  5 698 1122  5 143 1150  5 139 459 715 1156  5 681 1164  5 250 1179  5 996 1326  5 944 1327  5 966 1328  5 1086 1329  5 834 1330  5 589 1331  5 803 1332  5 1168 1333  5 824 1378  5 493 1379  5 282 1381  5 604 1384  5 313 1407  5 1287 174  6 1258 175  6 330 706 1180 176  6 1124 177  6 768 178  6 1192 179  6 910 180  6 703 181  6 1236 182  6 1500 183  6 1090 184  6 956 186  6 123 199 260 521 188  6 506 195  6 365 196  6 516 205  6 1172 207  6 402 208  6 480 324 209  6 1681 210  6 122 211  6 725 212  6 831 213  6 104 214  6 769 215  6 1091 216  6 625 218  6 764 219  6 851 220  6 993 221  6 945 223  6 1261 224  6 906 225  6 656 226  6 652 227  6 938 228  6 710 229  6 276 552 1304 230  6 567 232  6 152 427 237  6 1044 1182 239  6 153 290 1097 1353 240  6 184 538 639 243  6 120 245  6 224 518 829 248  6 312 250  6 180 472 1011 1327 251  6 144 586 791 253  6 107 319 624 254  6 544 255  6 115 256  6 157 257  6 285 259  6 156 260  6 140 261  6 148 525 856 262  6 386 263  6 199 264  6 172 265  6 126 162 643 266  6 395 267  6 130 268  6 110 488  6 219 247.5 681 1070  6 551 1102  6 878 273  7 623 274  7 876 281  7 201 282  7 1775 283  7 605 291  7 1019 310  8 141 311  8 125 312  8 198 1140  8 200 1325  8 575 186-A  8 149 1465  8 110 313  9 814 314  9 175 237 512 553 316  9 243 265 760 694 317  9 417 318  9 537 319  9 396 321  9 230 654  9 389 681  9 406 713  9 718  9 723  9 745  9 767  9 775  9 806  9 812  9 817  9 820  9 822  9 829  9 832  9 856  9 918  9 1054  9 1008 1055  9 701 1056  9 498 1068  9 849 1077  9 667 1088  9 760 1090  9 1106  9 784 1110  9 807 1116  9 828 1129  9 437 1131  9 563 1152  9 394 1153  9 404 1178  9 292 1198  9 1224  9 1226  9 1233  9 1261  9 1275  9 1277  9 1279  9 1286  9 1295  9 1302  9 1306  9 1320  9 823 1367  9 798 1368  9 859 1369  9 874 1370  9 773 1371  9 827 120  9b 483 126  9b 128 138 328 715 128  9b 688 129  9b 499 131  9b 1406 569  9b 198 571  9b 307 573  9b 277 577  9b 207 580  9b 179 582  9d 169 1109  9d 680 1113  9d 819 1133  9d 296 1159  9d 654 1171  9d 839 1177  9d 895 1182  9d 547 1255  9i 147 1154  9j 558 1173  9j 133 1190  9j 126 1254  9j 187 1282  9j 128 323 10 494 324 10 941 1215 1265 325 10 478 686 10 552 650 10a 960 666 10a 359 670 10a 650 900 10a 543 659 10b 576 697 10b 431 901 10b 816 902 10b 585 326 11 1336 327 11 904 2005 328 11 378 329 11 520 330 11 197 331 11 310 332 11 182 333 11 291 334 11 259 335 11 170 438 839 1059 336 11 223 337 11 103 166 272 671 504 11 178.5 543 11 158 684 11 645 897 11 1234 898 11 520 908 11 217 929 11 301 930 11 807 338 12 2111 791 342 12 288 343 13 1371 344 13 238 345 13 744 347 14 125 1059 14 507 1060 14 671 1065 14 531 1066 14 609 1096 14 449 1101 14 501 1157 14 252 1160 14 260 1183 14 549 1342 14 346 1343 14 838 1351 14 718 1352 14 548 1353 14 545 1354 14 750 1075 14a 833 350 17 498 903 17a 908 690 17b 367 357 20 152 358 21 556 359 21 176 360 21 819 361 21 186 364 21 581 365 21 971 665 21 507 679 21 751 685 21 756 736 21 499 907 21 867 366 22 432 367 22 701 368 22 434 906 22 896 927 22 850 928 22 1207 370 23 888 371 23 1138 879 23 1027 880 23 945 680 23a 356 661 24 764 668 24 679 883 24 767 379 26 760 380 26 773 381 26 520 397 27 243 398 27 392 400 27 1076 401 27 762 402 27 97 403 27 188 405 27 1591 406 27 99 407 27 127 441 743 957 27 1442 960 27 896 962 27 1213 967 27 1373 972 27 683 983 27 194 987 27 320 978 27a 570 968 27b 360 410 28 720 411 28 741 412 28 1271 413 28 1693 414 28 1608 415 28 1629 416 28 228 973 28 806 419 29 109 422 29 120 423 29 529 424 29 436 662 29 274.5 427 30 163 428 30 734 429 30 318 430 30 114 431 30 703 432 30 321 677 30a 141 433 31 159 508 31 119 651 31 258 876 31 363 434 32 737 435 32 198 453 35 917 454 35 1066 455 35 1013 548 35 280 959 35 861 956 35a 514 969 35a 515 494 39 1121 642 40 170 996 42 458 997 42 761 1016 42 536 547 42 652 985 42 1116 995 42 1080 998 42 639 999 42 458 1007 42 180 1008 42 1125 1009 42 706 771 42.9 465 1025 43 851 507 44 190 518 44 86 663 44 588 875 44 232 499 1285 877 44 475 904 44 392 909 44 144 660 45 410 683 45 335 878 45 288 689 45b 136 1010 46 1953 1011 46 994 1019 46 287 1021 46 232 1023 46 262 1024 46 281 1012 46a 173 1020 46a 135 1022 46a 189 542 47 366 671 49 1035 1365 50 909 1063 52 846 1092 52 838 1315 52 486 1316 53 602 1317 53 722 1319 53 1276 1142 53a 1314 1318 53a 1282 1086 54 488 1130 54 553 1137 54 582 1170 54 258 884 55 425 885 55 722 1081 55 622 1099 55 508 881 55a 847 882 55a 697 994 55a 1014 1026 56 1014 1027 56 785 1028 56 647 612 59 106 613 59 165 614 59 87 615 59 123 616 59 92 1074 59 303 1091 59 450 1093 59 472 1104 59 334 1108 59 117 204 456 1114 59 293 1117 59 437 1124 59 506 1138 59 271 1144 59 212 1168 59 780 1172 59 931 1185 59 241 1188 59 187 1200 59 231 1208 59 212 1221 59 198 197.5 522 1234 59 226 1253 59 110 190 407 1259 59 159 1265 59 192 1322 59 457 1323 59 297 1405 59 197 1406 59 169 1136 59a 325 1161 59a 459 1162 59a 237 1064 60 570 1167 60 345 1186 60 393 509 61 242 653 61 861 895 61 1207 701 62 475 1084 62 1165 1100 62 1133 1132 62 1259 1148 62 344 1155 62 617 1347 62 741 572 62a 397 634 62a 301 1340 62a 761 1341 62a 1149 1344 62a 543 1345 62a 459 982 63 762 986 64 626 570 65 210 691 65 840 695 65 497 1058 65 590 1095 65 484 1098 65 296 1346 65 406 506 67 132 673 67 280 896 67 648 664 67a 498 699 67a 253 505 67b 236.5 657 67b 581 674 67b 891 692 67b 284 899 67b 1092 649 68 1017 700 68 547 705 68a 487 574 69 207 1069 70 696 1348 70 1428 1349 70 846 1111 70a 508 1350 70a 873

Example 3 MGL ThermoFluor® Assay-Mutant

The ThermoFluor (TF) assay is a 384-well plate-based binding assay that measures thermal stability of proteins^(1,2). The experiments were carried out using instruments available from Johnson & Johnson Pharmaceutical Research & Development, LLC. TF dye used in all experiments was 1,8-ANS (Invitrogen: A-47). Final TF assay conditions used for MGL studies were 0.07 mg/ml of mutant MGL, 100 μM ANS, 200 mM NaCl, 0.001% Tween-20 in 50 mM PIPES (pH=7.0).

Screening compound plates contained 100% DMSO compound solutions at a single concentration. For follow-up concentration-response studies, compounds were arranged in a pre-dispensed plate (Greiner Bio-one: 781280), wherein compounds were serially diluted in 100% DMSO across 11 columns within a series. Columns 12 and 24 were used as DMSO reference and contained no compound. For both single and multiple compound concentration-response experiments, the compound aliquots (46 mL) were robotically predispensed directly into 384-well black assay plates (Abgene: TF-0384/k) using the Hummingbird liquid handler. Following compound dispension, protein and dye solutions were added to achieve the final assay volume of 3 μL. The assay solutions were overlayed with 1 μL of silicone oil (Fluka, type DC 200: 85411) to prevent evaporation.

Bar-coded assay plates were robotically loaded onto a thermostatically controlled PCR-type thermal block and then heated from 40 to 90° C. degrees at a ramp-rate of 1° C./min for all experiments. Fluorescence was measured by continuous illumination with UV light (Hamamatsu LC6), supplied via fiber optics and filtered through a band-pass filter (380-400 nm; >60D cutoff). Fluorescence emission of the entire 384-well plate was detected by measuring light intensity using a CCD camera (Sensys, Roper Scientific) filtered to detect 500±25 nm, resulting in simultaneous and independent readings of all 384 wells. A single image with 20-sec exposure time was collected at each temperature, and the sum of the pixel intensity in a given area of the assay plate was recorded vs temperature and fit to standard equations to yield the T_(m) ¹.

-   1. Pantoliano, M. W., Petrella, E. C., Kwasnoski, J. D., Lobanov, V.     S., Myslik, J., Graf, E., Carver, T., Asel, E., Springer, B. A.,     Lane, P., and Salemme, F. R. (2001) J Biomol Screen 6, 429-40. -   2. Matulis, D., Kranz, J. K., Salemme, F. R., and Todd, M. J. (2005)     Biochemistry 44, 5258-66.

The K_(d) values for compounds of Formula (I) were determined from a fit of the equation to the concentration-response plot of the fractional activity as a function of T_(n). For some experiments, quantitative NMR spectroscopy (qNMR) was used to measure concentration of the initial 100% DMSO compound solutions and, using the same fitting method, qK_(d) values were determined

BIOLOGICAL DATA TABLE 3 MGL mutant MGL mutant ThermoFluor qKd (μM) Cpd Example ThermoFluor Kd (μM) (using qNMR conc.) 1  1 0.00590 2  1 0.00049 3  1 2.50 4  1 0.143 5  1 0.0548 6  1 0.00360 7  1 0.0466 8  1 0.111 9  1 0.00248 10  1 0.556 11  1 0.454 12  1 0.0143 13  1 0.00300 14  1 0.250 15  1 0.286 22  1 >76.7 23  1 5.00 24  1 5.00 25  1 10.0 26  1 3.33 567  1 0.051 579  1 0.067 581  1 0.100 587  1 0.473 595  1 0.404 598  1 0.249 1071  1 0.025 1139  1 0.017 1147  1 0.003 1163  1 0.073 1174  1 0.015 1201  1 0.179 1248  1 0.043 1356  1 0.002 1357  1 0.002 1358  1 0.007 1359  1 0.008 1360  1 0.008 1361  1 0.003 1362  1 0.001 1363  1 0.014 1364  1 0.001 1366  1 0.012 1382  1 0.197 1408  1 0.012 487  1a 0.00240 586  1b 0.086 596  1b 0.628 603  1b 0.448 630  1b 0.195 1062  1b 0.100 1072  1b 0.007 1073  1b 0.087 1089  1b 0.009 0.006 1097  1b 0.032 1105  1b 0.023 1107  1b 0.003 1120  1b 0.020 1121  1b 0.042 1126  1b 0.008 1127  1b 0.098 1128  1b 0.018 1134  1b 0.009 1135  1b 0.015 1176  1b 0.161 1181  1b 0.278 1189  1b 0.153 1192  1b 0.035 1197  1b 0.065 1216  1b 0.022 1219  1b 0.025 1230  1b 0.009 1247  1b 0.650 1263  1b 0.215 1312  1b 0.008 1314  1b 0.001 1337  1b 0.040 1338  1b 0.015 1339  1b 0.013 1410  1b 0.014 656  1c 0.101 1079  1c 0.272 1184  1c 0.244 1199  1c 0.264 1141  1d 0.088 1151  1d 0.048 1158  1d 0.008 592  1e 0.500 1125  1e 0.037 1187  1e 0.197 629  1f 0.145 1180  1f 0.019 1313  1f 0.003 0.001 1409  1g 27  2 4.55 28  2 0.370 29  2 0.100 30  2 0.118 31  2 1.43 32  2 0.192 33  2 0.00910 34  2 0.588 35  2 0.0833 36  2 0.0370 37  2 0.100 38  2 0.182 39  2 0.0250 40  2 0.0242 41  2 0.00400 42  2 0.0833 47  2 0.0909 48  2 1.00 49  2 6.67 50  2 10.0 51  2 0.250 52  2 3.33 53  2 0.100 55  2 25.0 470  2 2.94 471  2 2.50 472  2 6.67 531  2 2.733 539  2 >31.2464 541  2 1.662 559  2 100.000 562  2 >31.2464 565  2 >31.2464 622  2 3.601 627  2 10.000 628  2 100.000 954  2 3.438 1266  2 0.032 1284  2 0.041 1404  2 >31.2464 1482  2 >31.2464 1483  2 >31.2464 1485  2 10.000 1464  2 >31.2464 61  3 0.0290 676  3 0.029 703  3 0.050 716  3 0.040 722  3 0.082 741  3 0.200 753  3 0.515 921  3 4.260 1067  3 0.007 1166  3 0.010 1235  3 0.124 1236  3 0.031 1242  3 0.197 1243  3 0.033 1246  3 0.042 1276  3 0.807 1283  3 0.523 1292  3 0.631 1383  3 0.108 1400  3 4.071 1401  3 1.250 1402  3 2.000 76  4 0.333 77  4 0.00909 78  4 0.0800 79  4 0.0266 80  4 49.5 81  4 0.0667 82  4 0.571 83  4 0.111 474  4 5.00 103  4 6.25 104  4 5.00 105  4 5.00 106  4 0.154 107  4 0.556 108  4 1.25 109  4 0.0333 110  4 5.00 111  4 10.0 496  4 0.287 558  4 0.333 618  4 0.080 619  4 0.172 620  4 0.154 621  4 0.263 623  4 1.000 624  4 0.880 625  4 >31.2464 626  4 5.018 150  5 0.00330 151  5 0.0250 158  5 0.476 161  5 0.0112 162  5 0.00067 163  5 0.00345 164  5 0.00111 166  5 0.00500 167  5 0.0558 168  5 0.0100 169  5 30.3 170  5 0.0606 171  5 0.708 172  5 0.100 475  5 0.0250 476  5 0.0667 477  5 2.00 478  5 2.00 479  5 6.67 298  5 2.91 113  5 1.11 114  5 0.00333 115  5 0.0370 116  5 2.00 489  5 0.0104 490  5 0.00840 485  5 0.0257 502  5 >76.6655 503  5 0.254 517  5 0.050 523  5 0.686 524  5 1.667 526  5 4.984 610  5 1.295 611  5 5.152 636  5 0.119 637  5 0.053 638  5 0.172 0.264 639  5 0.132 640  5 24.998 641  5 0.118 0.136 643  5 1.000 644  5 >76.6655 646  5 1.608 648  5 0.146 655  5 0.029 658  5 0.402 667  5 0.013 669  5 0.005 672  5 0.016 675  5 0.025 678  5 0.031 682  5 0.014 687  5 0.004 688  5 0.046 693  5 0.060 694  5 0.048 696  5 0.063 698  5 0.085 702  5 0.207 710  5 0.197 719  5 0.119 721  5 1.138 726  5 0.127 727  5 0.251 728  5 730  5 0.146 731  5 0.016 732  5 0.002 733  5 0.453 735  5 0.160 739  5 0.265 740  5 0.035 743  5 0.133 744  5 746  5 0.263 747  5 0.111 748  5 0.040 750  5 0.025 751  5 1.320 755  5 0.328 756  5 0.383 758  5 0.500 760  5 0.199 762  5 1.000 763  5 0.083 766  5 0.378 770  5 1.132 772  5 0.185 774  5 0.254 776  5 0.257 779  5 0.100 782  5 0.463 783  5 0.732 785  5 0.500 786  5 0.665 787  5 0.247 788  5 1.980 791  5 0.402 792  5 0.973 793  5 0.198 794  5 2.113 795  5 1.105 796  5 0.099 797  5 0.489 799  5 0.661 800  5 1.100 804  5 0.105 808  5 62.503 809  5 0.769 814  5 >31.0027 815  5 0.250 816  5 2.842 818  5 1.000 823  5 1.251 824  5 0.074 825  5 4.855 826  5 0.663 827  5 0.500 828  5 2.633 830  5 1.963 831  5 0.270 835  5 2.454 836  5 2.252 838  5 0.978 839  5 2.500 840  5 2.000 842  5 0.986 843  5 2.134 844  5 62.503 845  5 1.619 848  5 0.833 849  5 2.697 850  5 1.000 852  5 1.977 853  5 1.000 854  5 100.000 857  5 3.334 859  5 1.429 860  5 1.759 862  5 >21.8726 863  5 4.367 864  5 2.410 865  5 2.500 868  5 >23.126 873  5 9.198 874  5 8.461 887  5 0.009 888  5 0.000 889  5 0.002 890  5 0.001 891  5 0.008 892  5 0.007 893  5 0.005 894  5 0.006 905  5 0.044 910  5 1.331 912  5 1.319 915  5 5.000 923  5 9.931 925  5 >62.5029 926  5 9.443 946  5 1.693 947  5 0.653 952  5 0.019 953  5 >26.872 965  5 0.035 966  5 0.334 993  5 0.333 1017  5 0.049 1041  5 0.397 1042  5 5.000 1053  5 0.247 1082  5 0.003 1083  5 0.065 1119  5 0.020 1122  5 0.027 1123  5 1.351 1146  5 0.080 1150  5 0.013 1156  5 0.090 1179  5 0.005 1194  5 0.100 1202  5 0.065 1203  5 0.015 1223  5 0.111 1225  5 0.042 1245  5 0.317 1249  5 0.241 1271  5 1.000 1272  5 0.399 1287  5 0.495 1293  5 1.667 1298  5 0.474 1299  5 1.100 1300  5 3.334 1305  5 0.833 1307  5 4.207 1326  5 0.004 1327  5 0.005 1328  5 0.002 1329  5 0.006 1330  5 0.002 0.005 1331  5 0.010 1332  5 0.008 1333  5 0.040 1334  5 0.080 1378  5 0.025 1379  5 0.042 1381  5 0.083 1384  5 0.061 1385  5 0.206 1386  5 0.133 1392  5 0.659 1395  5 1.805 1396  5 0.317 1397  5 0.500 1403  5 1.688 1407  5 0.005 1412  5 0.241 1444  5 >31.0027 1445  5 >31.2464 1491  5 12.500 1434  5 53.753 1477  5 >31.2464 1432  5 >28.4381 1489  5 100.000 1490  5 >31.2464 1481  5 >31.2464 1436  5 100.000 1473  5 6.667 1475  5 >31.2464 1446  5 62.503 1447  5 3.334 1448  5 7.091 1449  5 3.194 1450  5 12.639 1451  5 >16.248 1452  5 5.424 1453  5 10.000 223  6 0.00670 225  6 0.0200 226  6 0.0200 229  6 0.0125 231  6 0.143 233  6 1.32 234  6 0.0476 235  6 0.588 236  6 0.200 237  6 0.00100 238  6 0.0333 239  6 0.00500 240  6 0.0232 241  6 0.00050 242  6 0.00400 243  6 0.0167 244  6 0.00200 245  6 0.00950 246  6 0.0167 247  6 0.00040 248  6 0.00670 249  6 0.0100 250  6 0.00170 251  6 0.0143 252  6 0.0500 253  6 0.0215 254  6 0.00590 255  6 0.0270 256  6 0.0333 257  6 0.00330 258  6 0.00330 259  6 0.00770 260  6 0.0200 261  6 0.00910 262  6 0.00250 263  6 0.00500 264  6 0.0100 265  6 0.0198 266  6 0.0160 267  6 0.0125 268  6 0.0250 488  6 0.321 1070  6 0.006 1102  6 0.006 295  7 0.833 296  7 0.476 297  7 0.333 308  8 10.0 309  8 0.253 310  8 0.250 311  8 0.0800 312  8 0.0250 480  8 >76.7 1057  8 0.016 1078  8 0.005 1085  8 0.008 1087  8 0.023 1094  8 0.012 1112  8 0.046 1118  8 0.053 1140  8 0.112 1143  8 0.070 1145  8 0.061 1169  8 0.053 1217  8 0.104 1222  8 0.068 1232  8 0.345 1256  8 0.393 1258  8 0.020 1262  8 0.278 1269  8 1.165 1308  8 2.056 1310  8 8.348 1324  8 0.016 1325  8 0.006 1335  8 0.011 1336  8 0.002 1398  8 0.182 1423  8 0.176 1424  8 0.124 1425  8 0.019 1426  8 0.029 1427  8 0.010 1428  8 0.018 1429  8 0.097 186-A  8 0.016 567-A  8 0.124 1478  8 >31.2464 1465  8 >31.2464 314  9 0.0392 316  9 0.0165 317  9 0.0100 318  9 0.0165 606  9 0.067 647  9 >31.2464 654  9 0.040 681  9 0.067 713  9 0.100 718  9 0.072 723  9 0.292 745  9 0.283 767  9 775  9 0.333 806  9 0.989 812  9 0.644 817  9 820  9 0.996 822  9 829  9 0.500 832  9 0.059 856  9 0.855 918  9 2.500 1054  9 0.001 0.001 1055  9 0.020 1056  9 0.012 1068  9 0.002 1077  9 0.020 1088  9 0.001 1090  9 0.010 1106  9 0.006 0.005 1110  9 0.010 1116  9 0.001 1129  9 0.074 1131  9 0.016 1152  9 0.007 1153  9 0.004 1178  9 0.238 1198  9 0.030 1224  9 0.189 1226  9 0.193 1233  9 0.190 1261  9 0.831 1277  9 2.722 1279  9 1.864 1286  9 0.032 1295  9 1.509 1302  9 2.500 1306  9 12.193 1320  9 0.015 1367  9 0.002 1368  9 0.001 1369  9 0.002 1370  9 0.013 1371  9 0.003 1372  9 0.002 1373  9 0.004 1413  9 0.003 1492  9 18.763 1499  9 60.618 126  9b 0.0921 128  9b 0.00400 129  9b 0.0100 130  9b 0.250 131  9b 0.0941 132  9b 0.250 568  9b 0.099 569  9b 0.059 571  9b 0.046 0.080 573  9b 0.100 577  9b 0.026 578  9b 0.195 580  9b 0.118 583  9b 0.051 590  9b 0.182 599  9b 0.481 566  9c 0.031 1375  9c 0.003 1421  9c 0.044 582  9d 0.119 588  9d 0.512 594  9d 0.743 1109  9d 0.022 1113  9d 0.010 1133  9d 0.036 1159  9d 0.003 1171  9d 0.024 1177  9d 0.088 1182  9d 0.210 633  9e 0.157 1115  9e 0.005 575  9f 0.083 576  9f 0.088 1080  9f 0.006 1374  9f 0.007 1376  9f 0.013 1419  9f 0.004 1420  9f 0.080 1422  9f 0.195 1165  9g 0.090 1210  9g 0.097 601  9i 0.527 602  9i 0.500 607  9i 1.000 608  9i 1.674 609  9i 1.000 980  9i 5.000 989  9i 1.250 990  9i 1.000 991  9i 0.200 1252  9i 0.386 1255  9i 0.048 1290  9i 0.643 1389  9i 0.422 1154  9j 0.006 1173  9j 0.007 1190  9j 0.008 1191  9j 0.011 1193  9j 0.017 1220  9j 0.015 1237  9j 0.064 1238  9j 0.125 1251  9j 0.146 1254  9j 0.100 1257  9j 0.009 1282  9j 0.200 1380  9j 0.246 323 10 0.00130 324 10 0.00040 325 10 0.0927 686 10 0.002 749 10 0.036 778 10 1.195 801 10 52.505 833 10 3.334 666 10a 0.002 0.003 670 10a 0.001 0.001 900 10a 0.001 0.001 659 10b 0.006 697 10b 0.024 901 10b 0.001 902 10b 0.004 326 11 0.00040 327 11 0.0137 328 11 0.0816 329 11 0.0626 330 11 0.438 331 11 0.00690 332 11 0.109 333 11 0.00390 334 11 0.132 335 11 0.00193 336 11 0.00950 337 11 0.0498 504 11 0.024 516 11 0.040 543 11 0.038 684 11 0.004 742 11 0.020 810 11 0.290 897 11 0.002 898 11 0.009 908 11 0.093 929 11 0.020 930 11 0.005 338 12 0.00110 343 13 0.00040 344 13 0.0100 345 13 0.00310 511 13 0.002 515 13 0.011 591 13 0.007 347 14 0.125 600 14 1.968 605 14 1.892 917 14 4.995 919 14 100.000 920 14 100.000 924 14 100.000 1059 14 0.066 1060 14 0.032 1065 14 0.036 1066 14 0.031 1096 14 0.080 1101 14 0.044 1157 14 0.179 1160 14 0.139 1183 14 0.067 1321 14 0.067 1342 14 0.136 1343 14 0.077 1351 14 0.043 1352 14 0.008 1353 14 0.018 1354 14 0.009 1075 14a 0.010 1149 14a 0.004 1175 14a 0.010 1205 14a 0.008 1196 14b 0.370 1204 14b 0.249 1211 14b 0.106 1241 14b 0.638 1244 14b 0.589 1209 14c 0.942 1213 14c 0.765 1294 14d 4.412 1303 14d 7.115 1443 14d >31.2464 1476 14d 7.208 546 17 12.365 1437 17 33.335 1486 17 >31.2464 538 17a 2.594 861 17a 2.625 903 17a 0.078 690 17b 0.104 357 20 0.238 358 21 0.0650 359 21 0.0829 360 21 0.0680 361 21 0.144 362 21 2.40 363 21 6.76 665 21 0.058 685 21 0.067 729 21 0.185 736 21 0.067 366 22 0.0353 367 22 0.0853 368 22 0.0551 370 23 0.00100 680 23a 0.053 1458 23a 100.000 372 24 0.0494 373 24 0.00550 374 24 0.00220 375 24 0.229 661 24 0.047 668 24 0.025 805 24 6.405 883 24 0.059 376 25 7.14 377 25 >76.7 378 25 >76.7 379 26 0.0400 393 26 0.0909 394 26 0.846 395 26 0.159 396 26 4.27 397 27 0.0333 398 27 0.0869 399 27 0.0408 401 27 0.00167 402 27 0.141 403 27 0.338 404 27 0.00170 405 27 0.00200 406 27 0.932 407 27 0.0988 408 27 1.94 409 27 2.03 483 27 0.0200 552 27 0.400 560 27 0.652 957 27 0.008 960 27 0.036 962 27 0.005 963 27 0.102 967 27 0.044 970 27 0.535 972 27 0.080 983 27 0.019 987 27 0.327 554 27a 1.985 978 27a 0.066 981 27a 0.937 958 27b 0.216 961 27b 0.576 968 27b 1.462 979 27b 1.143 984 27b 1.429 410 28 0.0333 411 28 0.0333 412 28 0.0100 413 28 0.00200 414 28 0.0250 415 28 0.00800 416 28 0.160 417 28 0.0667 418 28 0.500 555 28 2.000 975 28 2.000 974 28a 1.776 419 29 0.123 420 29 0.00500 421 29 0.00400 422 29 0.0532 423 29 0.00690 424 29 0.00941 425 29 0.200 426 29 0.250 662 29 0.100 427 30 0.0335 428 30 0.00330 429 30 0.0331 430 30 0.0667 432 30 0.0250 677 30a 0.432 790 30a 2.494 508 31 0.162 651 31 0.025 738 31 0.291 564 31a 10.000 976 31a 1.837 977 31a 19.999 807 31b 3.652 450 34 0.0500 452 34 0.200 453 35 0.0120 454 35 0.0147 455 35 0.00850 548 35 0.062 959 35 0.044 549 35a 0.060 551 35a 0.180 956 35a 0.081 969 35a 0.069 955 35b 1.111 964 35b 3.198 456 36 >76.7 457 37 4.82 458 37 6.67 459 37 3.33 460 37 9.10 491 39 0.100 492 39 0.167 493 39 0.0250 494 39 0.100 642 40 0.499 645 40 5.443 1488 41 >31.2464 1457 41 >31.2464 997 42 0.041 1006 42 0.667 1016 42 0.460 547 42 0.072 563 42 2.106 985 42 0.005 995 42 0.002 1007 42 0.259 1008 42 0.089 1009 42 0.589 1013 42 0.760 1014 42 0.903 1015 42 1.183 771 42 0.050 948 43 0.030 949 43 0.178 950 43 0.883 1025 43 0.066 507 44 0.317 520 44 2.000 522 44 4.708 525 44 2.500 527 44 10.000 532 44 2.331 533 44 10.000 537 44 3.334 663 44 0.020 715 44 0.167 717 44 0.067 734 44 1.255 752 44 0.095 765 44 3.094 875 44 0.010 877 44 0.100 904 44 0.633 909 44 0.325 913 44 1.000 1484 44 19.999 802 44a 1.667 837 44a 19.999 869 44a 6.202 872 44a 10.000 720 44b 0.347 757 44b 0.781 769 44b 2.000 784 44b 2.149 922 44b 3.890 514 45 0.727 519 45 0.962 660 45 0.065 683 45 0.039 878 45 0.088 1494 45a 7.377 803 45b 2.126 811 45b 3.334 1010 46 0.017 0.040 1011 46 0.124 1018 46 0.207 1019 46 0.166 0.132 1021 46 0.239 1023 46 0.143 1024 46 0.135 1267 46 0.741 1304 46 7.903 1309 46 6.540 1012 46a 3.337 1020 46a 3.004 1022 46a 0.228 1.061 1311 46a 67.499 529 47 0.317 530 47 0.089 542 47 0.014 553 47 0.372 556 47 0.097 557 47 0.114 561 47 0.542 1005 47 0.083 709 48 0.015 671 49 0.018 1365 50 0.002 1417 51 0.025 1418 51 0.054 1063 52 0.003 1092 52 0.005 1315 52 0.002 1316 53 0.002 1317 53 0.002 1319 53 0.001 1142 53a 0.001 1318 53a 0.000 597 54 0.153 1137 54 0.010 1170 54 0.014 1195 54 0.023 884 55 0.017 885 55 0.001 1081 55 0.019 1099 55 0.020 881 55a 0.006 882 55a 0.012 994 55a 0.002 724 55b 0.050 773 55b 0.040 1026 56 0.001 1027 56 0.012 1028 56 0.011 1033 56 0.000 1034 56 0.000 992 57 0.561 1430 57 50.003 1431 57 0.035 911 58 0.333 988 58 0.040 612 59 0.078 613 59 0.051 614 59 0.066 615 59 0.097 616 59 >76.6655 706 59 0.001 1074 59 0.011 1091 59 1.644 1093 59 0.240 1104 59 0.199 1108 59 0.063 1114 59 0.049 1117 59 0.214 1124 59 0.250 1138 59 0.018 1144 59 0.181 1168 59 0.067 1172 59 0.178 1185 59 1.318 1188 59 0.855 1200 59 0.500 1208 59 1.000 1221 59 0.081 1228 59 1.422 1234 59 0.394 1239 59 3.040 1240 59 2.488 1250 59 2.000 1253 59 0.088 1259 59 0.667 1265 59 0.660 1268 59 0.039 1273 59 1.827 1278 59 5.192 1280 59 6.422 1285 59 2.450 1288 59 2.159 1322 59 0.002 1323 59 0.004 1377 59 0.006 1405 59 0.002 1406 59 0.029 1161 59a 0.025 1162 59a 0.014 1260 59a 0.221 759 60 0.037 761 60 0.092 780 60 0.128 834 60 0.234 841 60 0.917 851 60 0.883 1064 60 0.018 1167 60 0.025 1186 60 0.035 1207 60 0.014 1231 60 0.131 1270 60 0.265 1274 60 0.248 1281 60 0.194 777 60a 0.048 789 60a 0.043 798 60a 0.004 858 60a 0.561 866 60a 0.824 1206 60a 0.018 1215 60a 0.006 1227 60a 0.011 1229 60a 0.011 1264 60a 0.251 1289 60a 0.130 1291 60a 0.179 1296 60a 0.197 932 60b 0.008 933 60b 0.034 934 60b 0.025 935 60b 0.034 936 60b 0.012 937 60b 0.096 938 60b 0.091 939 60b 0.302 940 60b 0.259 941 60b 0.389 942 60b 0.135 943 60b 1.045 944 60b 0.802 945 60b 0.083 509 61 0.033 653 61 0.011 895 61 0.000 593 62 0.010 701 62 0.008 1132 62 0.002 572 62a 0.030 634 62a 0.054 1340 62a 0.001 1341 62a 0.001 1344 62a 0.010 1345 62a 0.006 982 63 0.010 986 64 0.005 510 65 0.068 513 65 0.009 528 65 0.049 570 65 0.030 691 65 0.004 695 65 0.001 707 65 0.002 712 65 0.028 714 65 0.005 737 65 0.031 1058 65 0.007 1095 65 0.011 1098 65 0.031 1346 65 0.002 951 66 0.117 506 67 0.059 673 67 0.050 896 67 0.008 512 67a 0.050 664 67a 0.006 699 67a 0.041 505 67b 0.010 657 67b 0.002 0.002 674 67b 0.003 692 67b 0.005 899 67b 0.000 649 68 0.001 700 68 0.006 704 68a 0.017 705 68a 0.012 574 69 0.048 631 70 0.052 632 70 0.037 1069 70 0.028 1348 70 0.000 0.002 1349 70 0.005 0.006 1111 70a 0.009 1350 70a 0.001 1076 70b 0.020 1355 70b 0.002 1414 70c 0.003 1415 70c 0.011 1416 70c 0.015 711 71 0.050 813 71 0.499 1031 71 0.134 1032 71 1.100 1035 71 1.008 1046 71 0.064 1047 71 0.471 1048 71 0.146 1029 72 0.006 1030 72 0.033 1036 72 0.005 1037 72 0.022 1038 72 0.002 1039 72 0.007 1040 72 0.014 1043 72 0.055 1049 72 0.050 1050 72 0.085 1051 72 0.175 1052 72 0.065 1411 72 0.001 1044 72a 0.945 1045 72a 0.190 534 >76.6655 535 10.000 536 10.000 540 >31.2464 725 0.293 847 5.000 867 >31.2464 870 100.000 1487 >31.2464 1454 >31.2464 1505 >31.2464 1455 >31.2464 1456 >31.2464 1435 20.012 1504 1503 >31.2464 1502 >31.2464 1461  9i 100.000

In Vivo Methods Example 4 CFA-Induced Paw Radiant Heat Hypersensitivity

Each rat was placed in a test chamber on a warm glass surface and allowed to acclimate for approximately 10 min A radiant thermal stimulus (beam of light) was then focused through the glass onto the plantar surface of each hind paw in turn. The thermal stimulus was automatically shut off by a photoelectric relay when the paw was moved or when the cut-off time was reached (20 sec for radiant heat at ˜5 amps). An initial (baseline) response latency to the thermal stimulus was recorded for each animal prior to the injection of complete Freund's adjuvant (CFA). 24 h following intraplantar CFA injection, the response latency of the animal to the thermal stimulus was then re-evaluated and compared to the animal's baseline response time. Only rats that exhibited at least a 25% reduction in response latency (i.e., were hyperalgesic) were included in further analysis. Immediately following the post-CFA latency assessment, the indicated test compound or vehicle was administered orally. Post-compound treatment withdrawal latencies were assessed at fixed time intervals, typically 30, 60, 120, 180, and 300 min.

The percent reversal (% R) of hypersensitivity was calculated in one of two different ways: 1) using group mean values or 2) using individual animal values. More specifically:

Method 1

For all compounds, the % R of hypersensitivity was calculated using the mean value for groups of animals at each time point according to the following formula: % reversal=[(group treatment response−group CFA response)/(group baseline response−group CFA response)]×100 Results are given for the maximum % reversal observed for each compound at any time point tested.

Method 2.

For some compounds, the % R of hypersensitivity was calculated separately for each animal according to the following formula: % reversal=[(individual treatment response−individual CFA response)/(individual baseline response−individual CFA response)]×100. Results are given as a mean of the maximum % reversal values calculated for each individual animal.

BIOLOGICAL TABLE 4 CFA thermal hypersensitivity dose last time Method 1: Method 2: (mg/kg, no. of point peak % peak % cmpd p.o.) vehicle animals (min) reversal reversal 5 30 HPβCD 9 180 96.6 100.5 7 30 HPβCD 8 180 77.8 76.2 9 30 HPβCD 8 180 75.4 77.4 39 30 HPβCD 8 180 39.1 39.7 126 10 HPβCD 8 300 40.8 40.4 126 30 HPβCD 8 300 51 79.5 229 30 HPβCD 8 300 55.8 56.6 232 30 HPβCD 8 180 9.6 8 239 30 HPβCD 8 300 81.8 87.5 240 30 HPβCD 8 300 43 44.4 250 30 HPβCD 8 300 41.7 41.9 251 30 HPβCD 8 300 35.1 38.5 253 30 HPβCD 8 300 64.3 87.2 261 30 HPβCD 8 300 26.4 27.5 266 30 HPβCD 8 300 50.5 56.1 314 30 HPβCD 8 180 41 41.2 316 30 HPβCD 8 180 69.3 70.8 317 30 HPβCD 8 300 43 318 30 HPβCD 8 300 44.7 324 30 HPβCD 8 300 48.7 55.8 325 30 HPβCD 9 300 62.1 63.1 326 30 HPβCD 8 300 17.3 17.5 331 30 HPβCD 8 300 14.3 333 30 HPβCD 8 300 27.7 335 30 HPβCD 8 300 108.2 135.2 337 30 HPβCD 9 300 14.3 17.6 345 30 HPβCD 8 300 25 26.3 407 30 HPβCD 8 300 1.6 1.4 485 30 HPβCD 8 300 34.4 32.3 487 30 HPβCD 8 300 109.2 166.5 488 30 HPβCD 8 300 78 85.5 489 30 HPβCD 8 180 27.1 43.5 490 30 HPβCD 8 300 18.4 19.7 509 30 HPβCD 8 300 17.8 567 30 HPβCD 8 300 63.1 571 30 HPβCD 8 300 133.2 572 30 HPβCD 8 300 −5.1 650 30 HPβCD 8 300 29.9 653 30 HPβCD 8 300 −10.7 657 30 HPβCD 8 300 66 662 30 HPβCD 8 300 21 24 663 30 HPβCD 8 300 33.9 666 30 HPβCD 8 300 −3.1 670 30 HPβCD 8 300 20.9 674 30 HPβCD 8 300 57.7 895 30 HPβCD 8 300 23.4 899 30 HPβCD 8 300 80.1 900 30 HPβCD 8 300 8.5 1010 30 HPβCD 8 300 23.4 1054 30 HPβCD 8 300 27.6 1070 30 HPβCD 8 300 25.7 23.1 1088 30 HPβCD 8 300 35.3 1102 30 HPβCD 8 300 38 45.3 1106 30 HPβCD 8 300 45 1108 30 HPβCD 8 300 84.9 99.2 1117 30 HPβCD 8 300 23.2 1124 30 HPβCD 8 300 88.1 1125 30 HPβCD 8 300 64.5 90.3 1132 30 HPβCD 8 300 0 1139 30 HPβCD 8 300 43.8 1141 30 HPβCD 8 300 5.7 1174 30 HPβCD 8 300 13.6 1187 30 HPβCD 8 300 16.3 1221 30 HPβCD 8 300 44.7 46.7 1337 30 HPβCD 8 300 6.7 1338 30 HPβCD 8 300 86.3 1340 30 HPβCD 8 300 13.1 1341 30 HPβCD 8 300 7.5 1357 30 HPβCD 8 300 51 46.1 1358 30 HPβCD 8 300 25.4 1359 30 HPβCD 8 300 5.1 12.7 1360 30 HPβCD 8 300 40.5 40.5 1362 30 HPβCD 8 300 185.9 1363 30 HPβCD 8 300 69.7 1364 30 HPβCD 8 300 17 1366 30 HPβCD 8 300 47.1

Example 5 CFA-Induced Paw Pressure Hypersensitivity

Prior to testing, rats were acclimated to the handling procedure twice a day for a period of two days. The test consisted of placing the left hindpaw on a Teflon® (polytetrafluoroethylene) coated platform and applying a linearly increasing mechanical force (constant rate of 12.5 mmHg/s) in between the third and fourth metatarsal of the dorsum of the rat's hindpaw, with a dome-tipped plinth (0.7 mm in radius), using an analgesy-meter (Stoelting, Chicago, Ill.), also known as a Randall-Selitto apparatus. The endpoint was automatically reached upon hindpaw withdrawal, and the terminal force was noted (in grams). An initial (baseline) response threshold to the mechanical stimulus was recorded for each animal prior to the injection of complete Freund's adjuvant (CFA). Forty hr following intraplantar CFA injection, the response threshold of the animal to the mechanical stimulus was re-evaluated and compared to the animal's baseline response threshold. A response was defined as a withdrawal of the hindpaw, a struggling to remove the hindpaw or vocalization. Only rats that exhibited at least a 25% reduction in response threshold (i.e., hyperalgesia) were included in further analysis. Immediately following the post-CFA threshold assessment, rats were administered the indicated test compound or vehicle. Post-treatment withdrawal thresholds were assessed at 1 h. Paw withdrawal thresholds were converted to percent reversal of hypersensitivity according to the following formula: % reversal=[(post treatment response-predose response)/(baseline response-predose response)]×100.

BIOLOGICAL TABLE 5 CFA induced paw pressure hypersensitivity route of time percent cmpd N dose administration vehicle (h) reversal 487 8 30 s.c. HPβCD 1 61.8 1362 10 30 s.c. HPβCD 1 56.7

Example 6 Chronic Constriction Injury (CCI)-Induced Model of Neuropathic Pain Cold Acetone-Hypersensitivity Test

Male Sprague-Dawley rats (225-450 g) were used to evaluate the ability of selected compounds to reverse CCI-induced cold hypersensitivity. Four loose ligatures of 4-0 chromic gut were surgically placed around the left sciatic nerve under inhalation anesthesia as described by Bennett et al. (Bennett G J, Xie Y K. Pain 1988, 33(1): 87-107). Fourteen to 35 days following CCI surgery, subjects were placed in elevated observation chambers containing wire mesh floors, and five applications of acetone (0.05 mL/application separated by about 5 min) were spritzed onto the plantar surface of the paw using a multidose syringe. An abrupt withdrawal or lifting of the paw was considered a positive response. The number of positive responses was recorded for each rat over the five trials. Following baseline withdrawal determinations, compounds were administered in the indicated vehicle, by the indicated route (see Table 6). The number of withdrawals was re-determined 1 to 4 h after compound administration. Results are presented as a percent inhibition of shakes, which was calculated for each subject as [1−(test compound withdrawals/pre-test withdrawals)]×100 and then averaged by treatment.

BIOLOGICAL TABLE 6 CCI induced cold sensitivity dose route of last time peak percent cpd N (mg/kg) administration vehicle point (h) inhibition 5 9 30 p.o. HPβCD 4 26.7 335 9 30 p.o. HPβCD 4 100 487 9 30 p.o. HPβCD 4 100 1362 6 3 p.o. HPβCD 4 70.0

Example 7 Spinal Nerve Ligation (SNL) Model of Neuropathic Pain Tactile Allodynia Test

For lumbar 5 (L₅) spinal nerve ligation (SNL) studies, anesthesia was induced and maintained on isoflurane inhalation. Fur was clipped over the dorsal pelvic area, and a 2-cm skin incision was made just left of midline over the dorsal aspect of the L₄-S₂ spinal segments, followed by separation of the paraspinal muscles from spinous processes. The transverse process of L₆ was then carefully removed, and the L₅ spinal nerve was identified. The left L₅ spinal nerve was then ligated tightly with 6-0 silk thread, the muscle was sutured with 4-0 vicryl, and the skin was closed with wound clips. Following surgery, s.c. saline (5 mL) was administered.

Behavioral testing was performed four weeks post-ligation. Following baseline von Frey determinations to verify the presence of mechanical allodynia, L₅ SNL rats were orally administered the indicated vehicle or drug. Tactile allodynia was quantified at 30, 60, 100, 180 and 300 min post-dosing by recording the force at which the paw ipsilateral to the nerve ligation was withdrawn from the application of a series of calibrated von Frey filaments (0.4, 0.6, 1.0, 2.0, 4, 6, 8 and 15 g; Stoelting; Wood Dale, Ill.). Beginning at an intermediate stiffness (2.0 g), filaments were applied to the mid-plantar hind paw for approximately 5 seconds. to determine the response threshold, a brisk paw withdrawal led to the presentation of the next lighter stimulus, whereas a lack of a withdrawal response led to the presentation of the next stronger stimulus. A total of four responses after the first threshold detection were collected. The 50% withdrawal thresholds were interpolated by the method of Dixon, Efficient analysis of experimental observations. Annu. Rev. Pharmacol. Toxicol. 20:441-462 (1980) as modified by Chaplan et. al., Quantitative assessment of tactile allodynia in the rat paw, J. Neurosci. Methods. 53(1):55-63 (1994) and when response thresholds fell above or below the range of detection, respective values of 15.0 or 0.25 g were assigned. Threshold data from von Frey filament testing were reported as withdrawal threshold in grams. Data were normalized and results are presented as % MPE (maximum possible effect) of the drug calculated according to the following formula:

${\%\mspace{14mu}{MPE}} = {\frac{{x\mspace{14mu} g\text{/}{force}} - {{baseline}\mspace{14mu} g\text{/}{force}}}{{15\mspace{14mu} g\text{/}{force}} - {{baseline}\mspace{14mu} g\text{/}{force}}} \times 100}$

BIOLOGICAL TABLE 7 Spinal nerve ligation - tactile allodynia dose route of last time peak % cmpd N (mg/kg) administration vehicle point (h) MPE 335 6 30 p.o. HPβCD 4 50.1 487 6 30 p.o. HPβCD 4 61.2 1362 6 30 p.o. HPβCD 4 84.3

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents. 

We claim:
 1. A compound of Formula (I)

selected from the group consisting of: a compound wherein Y is phenyl, Z is 4-(3-trifluoromethylphenyl)phenyl, and s is 0; a compound wherein Y is penta-deuterated phenyl, Z is 4-(3-trifluoromethylphenyl)phenyl, and s is 0; a compound wherein Y is phenyl, Z is 4-(2-trifluoromethoxyphenyl)phenyl, and s is 0; a compound wherein Y is phenyl, Z is 4-(3-dimethylaminosulfonylamino-phenyl)phenyl, and s is 0; a compound wherein Y is phenyl, Z is 1-(4-trifluoromethylphenyl)-1H-indol-5-yl, and s is 0; a compound wherein Y is phenyl, Z is 4-(2-trifluoromethylphenyl)phenyl, and s is 0; a compound wherein Y is phenyl, Z is 4-(4-chloro-3-trifluoromethylphenyl)phenyl, and s is 0; a compound wherein Y is phenyl, Z is 1-phenyl-indol-5-yl, and s is 0; a compound wherein Y is phenyl, Z is 3-methyl-4-(3-trifluoromethylphenyl)phenyl, and s is 0; a compound wherein Y is phenyl, Z is 2-fluoro-4-(3-trifluoromethylphenyl)phenyl, and s is 0; a compound wherein Y is phenyl, Z is 3-methoxy-4-(3-trifluoromethylphenyl)phenyl, and s is 0; a compound wherein Y is phenyl, Z is 2-chloro-4-(3-trifluoromethylphenyl)phenyl, and s is 0; a compound wherein Y is phenyl, Z is 2-methyl-4-(3-chloro-4-fluorophenyl)phenyl, and s is 0; a compound wherein Y is phenyl, Z is 3-methyl-4-(3-chloro-4-fluorophenyl)phenyl, and s is 0; a compound wherein Y is phenyl, Z is 3-methyl-4-(4-chloro-3-trifluoromethylphenyl)phenyl, and s is 0; a compound wherein Y is phenyl, Z is 3-methoxy-4-(3-chloro-4-fluorophenyl)phenyl, and s is 0; a compound wherein Y is phenyl, Z is 3-methoxy-4-(4-chloro-3-trifluoromethylphenyl)phenyl, and s is 0; a compound wherein Y is phenyl, Z is 2-chloro-4-(3-chloro-4-fluorophenyl)phenyl, and s is 0; a compound wherein Y is phenyl, 3-chloro-6-phenyl-benzothien-2-yl, and s is 0; a compound wherein Y is phenyl, Z is 1-(4-cyano-3-methylphenyl)-indol-5-yl, and s is 0; a compound wherein Y is phenyl, Z is 1-(4-fluorophenyl)-indol-5-yl, and s is 0; a compound wherein Y is penta-deuterated phenyl, Z is 1-(4-fluorophenyl)-indol-5-yl, and s is 0; a compound wherein Y is phenyl, Z is 1-(3,4,5-trifluorophenyl)-indol-5-yl, and s is 0; a compound wherein Y is phenyl, Z is 3-methyl-5-phenyl-benzo[b]thien-2-yl, and s is 0; a compound wherein Y is phenyl, Z is 1-(3,4-difluorophenyl)-indol-5-yl, and s is 0; a compound wherein Y is phenyl, Z is 3-(3-trifluoromethylphenyl)-1H-indol-6-yl, and s is 0; a compound wherein Y is phenyl, Z is 1-phenyl-1H-indazol-5-yl, and s is 0; a compound wherein Y is phenyl, Z is 2-chloro-4-phenyl-phenyl, and s is 0; a compound wherein Y is phenyl, Z is 3-methyl-4-phenyl-phenyl, and s is 0; a compound wherein Y is phenyl, Z is 2-fluoro-4-phenyl-phenyl, and s is 0; a compound wherein Y is phenyl, Z is 3-methoxy-4-phenyl-phenyl, and s is 0; or a pharmaceutically acceptable salt form thereof.
 2. A pharmaceutical composition comprising a compound of claim 1 and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient and a pharmaceutically acceptable diluent.
 3. A pharmaceutical composition of claim 2, wherein the composition is a solid oral dosage form.
 4. A pharmaceutical composition of claim 2, wherein the composition is a syrup, an elixir or a suspension. 